CN108473485A - 喹啉-2-酮衍生物 - Google Patents
喹啉-2-酮衍生物 Download PDFInfo
- Publication number
- CN108473485A CN108473485A CN201680078446.3A CN201680078446A CN108473485A CN 108473485 A CN108473485 A CN 108473485A CN 201680078446 A CN201680078446 A CN 201680078446A CN 108473485 A CN108473485 A CN 108473485A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- quinoline
- triazole
- fluoro
- carbonyls
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 172
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 17
- 201000011510 cancer Diseases 0.000 claims abstract description 13
- 239000002585 base Substances 0.000 claims description 435
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 164
- -1 pyrimidine radicals Chemical class 0.000 claims description 135
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 112
- 239000000203 mixture Substances 0.000 claims description 111
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 88
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 83
- 150000003839 salts Chemical class 0.000 claims description 73
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 59
- PDFKFLNYRFAWOA-UHFFFAOYSA-N 1-fluoroquinolin-2-one Chemical class C1=CC=C2C=CC(=O)N(F)C2=C1 PDFKFLNYRFAWOA-UHFFFAOYSA-N 0.000 claims description 50
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 48
- 229940111121 antirheumatic drug quinolines Drugs 0.000 claims description 43
- 229910052757 nitrogen Inorganic materials 0.000 claims description 38
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 32
- 239000000470 constituent Substances 0.000 claims description 31
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 31
- 229910052731 fluorine Inorganic materials 0.000 claims description 29
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 29
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 25
- 229910052801 chlorine Inorganic materials 0.000 claims description 24
- 235000019253 formic acid Nutrition 0.000 claims description 24
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 21
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 20
- 150000001408 amides Chemical class 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 150000005054 naphthyridines Chemical class 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- GTINRJGGSAKCEO-ZCFIWIBFSA-N (3r)-3-(methoxymethyl)pyrrolidine Chemical compound COC[C@@H]1CCNC1 GTINRJGGSAKCEO-ZCFIWIBFSA-N 0.000 claims description 17
- GTINRJGGSAKCEO-LURJTMIESA-N (3s)-3-(methoxymethyl)pyrrolidine Chemical compound COC[C@H]1CCNC1 GTINRJGGSAKCEO-LURJTMIESA-N 0.000 claims description 17
- 239000003513 alkali Substances 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 150000003852 triazoles Chemical class 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 15
- 229940095102 methyl benzoate Drugs 0.000 claims description 15
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- 238000006467 substitution reaction Methods 0.000 claims description 14
- QGRRJTQMMXJUNP-UHFFFAOYSA-N 1-pyrrolidin-1-ylpyrrolidine Chemical compound C1CCCN1N1CCCC1 QGRRJTQMMXJUNP-UHFFFAOYSA-N 0.000 claims description 13
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 13
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 13
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims description 12
- 239000012453 solvate Substances 0.000 claims description 12
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- OTWVFHZMWFGHSJ-UHFFFAOYSA-N 1-fluoropyrrolidine Chemical class FN1CCCC1 OTWVFHZMWFGHSJ-UHFFFAOYSA-N 0.000 claims description 10
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 10
- 125000003566 oxetanyl group Chemical group 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 230000008859 change Effects 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- KIWSYRHAAPLJFJ-DNZSEPECSA-N n-[(e,2z)-4-ethyl-2-hydroxyimino-5-nitrohex-3-enyl]pyridine-3-carboxamide Chemical compound [O-][N+](=O)C(C)C(/CC)=C/C(=N/O)/CNC(=O)C1=CC=CN=C1 KIWSYRHAAPLJFJ-DNZSEPECSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- WITMXBRCQWOZPX-UHFFFAOYSA-N 1-phenylpyrazole Chemical class C1=CC=NN1C1=CC=CC=C1 WITMXBRCQWOZPX-UHFFFAOYSA-N 0.000 claims description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 150000003053 piperidines Chemical class 0.000 claims description 8
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 7
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 7
- 125000002757 morpholinyl group Chemical group 0.000 claims description 7
- 125000004193 piperazinyl group Chemical group 0.000 claims description 7
- 125000005936 piperidyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 6
- JHHZLHWJQPUNKB-SCSAIBSYSA-N (3r)-pyrrolidin-3-ol Chemical compound O[C@@H]1CCNC1 JHHZLHWJQPUNKB-SCSAIBSYSA-N 0.000 claims description 5
- ZENKESXKWBIZCV-UHFFFAOYSA-N 2,2,4,4-tetrafluoro-1,3-benzodioxin-6-amine Chemical group O1C(F)(F)OC(F)(F)C2=CC(N)=CC=C21 ZENKESXKWBIZCV-UHFFFAOYSA-N 0.000 claims description 5
- 125000000872 2-diethylaminoethoxy group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 claims description 5
- GTINRJGGSAKCEO-UHFFFAOYSA-N 3-(methoxymethyl)pyrrolidine Chemical compound COCC1CCNC1 GTINRJGGSAKCEO-UHFFFAOYSA-N 0.000 claims description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
- 241000972349 Ocoa Species 0.000 claims description 5
- 125000002393 azetidinyl group Chemical group 0.000 claims description 5
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 5
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- MRWRHHSVHWCISU-ZCFIWIBFSA-N (3r)-3-methoxypiperidine Chemical compound CO[C@@H]1CCCNC1 MRWRHHSVHWCISU-ZCFIWIBFSA-N 0.000 claims description 4
- MRWRHHSVHWCISU-LURJTMIESA-N (3s)-3-methoxypiperidine Chemical compound CO[C@H]1CCCNC1 MRWRHHSVHWCISU-LURJTMIESA-N 0.000 claims description 4
- CHPRFKYDQRKRRK-LURJTMIESA-N (S)-2-(methoxymethyl)pyrrolidine Chemical compound COC[C@@H]1CCCN1 CHPRFKYDQRKRRK-LURJTMIESA-N 0.000 claims description 4
- KVTUSMPNLUCCQO-UHFFFAOYSA-N 3,3-difluoropyrrolidine Chemical compound FC1(F)CCNC1 KVTUSMPNLUCCQO-UHFFFAOYSA-N 0.000 claims description 4
- ZEYSHALLPAKUHG-UHFFFAOYSA-N 4-methoxypiperidine Chemical compound COC1CCNCC1 ZEYSHALLPAKUHG-UHFFFAOYSA-N 0.000 claims description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 claims description 4
- AVAWMINJNRAQFS-UHFFFAOYSA-N n,n-dimethylpyrrolidin-3-amine Chemical compound CN(C)C1CCNC1 AVAWMINJNRAQFS-UHFFFAOYSA-N 0.000 claims description 4
- PRAYXGYYVXRDDW-UHFFFAOYSA-N piperidin-2-ylmethanol Chemical compound OCC1CCCCN1 PRAYXGYYVXRDDW-UHFFFAOYSA-N 0.000 claims description 4
- 229940080818 propionamide Drugs 0.000 claims description 4
- 150000003233 pyrroles Chemical class 0.000 claims description 4
- 238000003797 solvolysis reaction Methods 0.000 claims description 4
- JHHZLHWJQPUNKB-BYPYZUCNSA-N (3s)-pyrrolidin-3-ol Chemical compound O[C@H]1CCNC1 JHHZLHWJQPUNKB-BYPYZUCNSA-N 0.000 claims description 3
- DCYUSJCEVXJZCY-UHFFFAOYSA-N 1-fluoro-2h-quinoline Chemical class C1=CC=C2N(F)CC=CC2=C1 DCYUSJCEVXJZCY-UHFFFAOYSA-N 0.000 claims description 3
- 230000029936 alkylation Effects 0.000 claims description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- CHPRFKYDQRKRRK-ZCFIWIBFSA-N (2r)-2-(methoxymethyl)pyrrolidine Chemical compound COC[C@H]1CCCN1 CHPRFKYDQRKRRK-ZCFIWIBFSA-N 0.000 claims description 2
- UJJLJRQIPMGXEZ-BYPYZUCNSA-N (2s)-oxolane-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCO1 UJJLJRQIPMGXEZ-BYPYZUCNSA-N 0.000 claims description 2
- DLUDAUJQMXTXGQ-RQJHMYQMSA-N (3ar,6ar)-5-methyl-2,3,3a,4,6,6a-hexahydro-1h-pyrrolo[2,3-c]pyrrole Chemical class C1CN[C@H]2CN(C)C[C@H]21 DLUDAUJQMXTXGQ-RQJHMYQMSA-N 0.000 claims description 2
- NGZYRKGJWYJGRS-RXMQYKEDSA-N (3r)-n-methylpyrrolidin-3-amine Chemical compound CN[C@@H]1CCNC1 NGZYRKGJWYJGRS-RXMQYKEDSA-N 0.000 claims description 2
- CALDMMCNNFPJSI-CRCLSJGQSA-N (3r,5s)-5-(hydroxymethyl)pyrrolidin-3-ol Chemical compound OC[C@@H]1C[C@@H](O)CN1 CALDMMCNNFPJSI-CRCLSJGQSA-N 0.000 claims description 2
- NGZYRKGJWYJGRS-YFKPBYRVSA-N (3s)-n-methylpyrrolidin-3-amine Chemical compound CN[C@H]1CCNC1 NGZYRKGJWYJGRS-YFKPBYRVSA-N 0.000 claims description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- IOIDFMWCCIVZJC-UHFFFAOYSA-N 3-(1-phenyltriazol-4-yl)-1H-quinolin-2-one Chemical class O=c1[nH]c2ccccc2cc1-c1cn(nn1)-c1ccccc1 IOIDFMWCCIVZJC-UHFFFAOYSA-N 0.000 claims description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 2
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical class CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 claims description 2
- UCDFBOLUCCNTDQ-RXMQYKEDSA-N [(3r)-morpholin-3-yl]methanol Chemical compound OC[C@@H]1COCCN1 UCDFBOLUCCNTDQ-RXMQYKEDSA-N 0.000 claims description 2
- UCDFBOLUCCNTDQ-YFKPBYRVSA-N [(3s)-morpholin-3-yl]methanol Chemical compound OC[C@H]1COCCN1 UCDFBOLUCCNTDQ-YFKPBYRVSA-N 0.000 claims description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 2
- 238000004806 packaging method and process Methods 0.000 claims description 2
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 claims description 2
- 238000012545 processing Methods 0.000 claims description 2
- QOTUIIJRVXKSJU-UHFFFAOYSA-N pyrrolidin-3-ylmethanol Chemical compound OCC1CCNC1 QOTUIIJRVXKSJU-UHFFFAOYSA-N 0.000 claims description 2
- 150000003235 pyrrolidines Chemical class 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- UJJLJRQIPMGXEZ-SCSAIBSYSA-N tetrahydrofuran-2-carboxylic acid Chemical compound OC(=O)[C@H]1CCCO1 UJJLJRQIPMGXEZ-SCSAIBSYSA-N 0.000 claims description 2
- SEKGKTDOBOZQAV-UHFFFAOYSA-N naphthalene;pyridine Chemical compound C1=CC=NC=C1.C1=CC=CC2=CC=CC=C21 SEKGKTDOBOZQAV-UHFFFAOYSA-N 0.000 claims 3
- 230000001093 anti-cancer Effects 0.000 claims 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 1
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- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 abstract description 5
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- 239000003112 inhibitor Substances 0.000 abstract description 4
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- 235000019198 oils Nutrition 0.000 description 14
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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Abstract
式(I)的化合物,其中X1、X2、X3、X4、R1、R2、R3、Q和Y具有权利要求1中所示的含义,是c‑Kit激酶的抑制剂,且可以用于治疗癌症。
Description
发明背景
本发明的目的是发现具有有价值特性的新型化合物,特别是可以用于制备药物的那些化合物。
本发明涉及跨越GIST(胃肠道间质瘤)患者中可能出现的广泛范围的c-KIT突变和继发性突变(外显子13中的V654A继发性耐药突变)抑制c-KIT激酶的喹啉-2-酮衍生物。
因此,本发明的化合物可用于治疗疾病诸如癌症。
本发明还提供了用于制备这些化合物的方法,包含这些化合物的药物组合物,用于治疗疾病的化合物和利用包含这些化合物的药物组合物治疗疾病的方法。
受体酪氨酸激酶c-KIT的突变形式是几种癌症中的“驱动因子”,并且是治疗的有吸引力的靶标。尽管从使用KIT激酶活性的抑制剂、诸如伊马替尼已经获得益处(尤其是在GIST中),但是会发生具有某些致癌突变的原发性耐药性。此外,由于继发性突变,耐药性频繁发展(L.K.Ashman & R.Griffith (2013) Expert Opinion on InvestigationalDrugs, 22:1, 103-115)。
L.L. Chen等人在Cancer res.2004; 64:5913-5919中描述了“KIT激酶结构域1中的错义突变与胃肠道间质瘤中的伊马替尼耐药性相关”。
K.G. Roberts等人在Mol.Cancer Ther.2007; 6:1159-1166中描述了“由V654A突变赋予的对c-KIT激酶抑制剂的耐药性”。
胃肠道间质瘤(GIST)是胃肠(GI)道的最常见的间充质肿瘤。
GIST被定义为c-KIT (CD117,干细胞因子受体)-阳性的间充质梭形细胞或上皮样赘生物。
GIST通常具有KIT基因的原发性活化突变(90%),导致受体酪氨酸激酶c-KIT的配体非依赖性活化,使得肿瘤依赖于致癌KIT活性。
伊马替尼治疗具有原发性突变的GIST具有~ 70%的初始反应率,但在几乎所有肿瘤中都出现继发性耐药性。
近似60-70%的伊马替尼失败的患者在c-KIT中携带继发性V654A耐药突变。
对于开发针对KIT V654A耐药性突变的安全和特异性抑制剂存在很高的未满足的医学需求。
已经发现根据本发明的化合物及其盐具有非常有价值的药理学特性,同时被良好耐受。
本发明具体涉及抑制c-KIT激酶、优选c-KIT激酶的突变体V654A的式I的化合物。
此外,式I的化合物抑制PDGFRα(V651D)。PDGFRα的功能获得性突变似乎在没有KIT突变的GIST的发展中发挥重要作用(S.Hirota等人, Gastroenterology 2003;125:660-667)。
宿主或患者可属于任何哺乳动物物种,例如灵长类物种,特别是人;啮齿类,包括小鼠、大鼠和仓鼠;兔;马、牛、狗、猫等。动物模型是实验研究所关注的,提供用于治疗人类疾病的模型。
可通过体外测试来测定具体细胞对用根据本发明的化合物治疗的易感性。通常,将细胞培养物与各种浓度的本发明化合物组合一段时间,所述时间足以允许活性剂诸如抗IgM诱导细胞反应诸如表面标志物的表达,通常在约一小时和一周之间。可使用来自血液或来自活组织检查样品的培养细胞实施体外测试。所表达的表面标志物的量通过流式细胞术使用识别所述标志物的特异性抗体来评价。
剂量根据所用的具体化合物、具体疾病、患者状态等而改变。治疗剂量通常足以显著减少靶组织中不期望的细胞群体,同时患者的生存力得以维持。治疗通常持续直至已出现显著减少,例如细胞负荷减少至少约50%,并且治疗可持续直至体内基本不再检测出不期望的细胞。
现有技术
T. N. Glasnov和C. O. Kappe在QSAR Comb. Sci 2007, 26, 1261中描述了化合物6,7-二甲氧基-3-(1-苯基-1H-1,2,3-三唑-4-基)喹啉-2(1H)-酮
具有荧光特征。
二氢萘啶类化合物和相关化合物在WO2013/184119A1中被描述为c-Kit突变体(包括V654A突变体)的抑制剂。
发明概述
本发明涉及式I的化合物
其中
X1、X2、X3、X4 各自彼此独立地表示CH或N,
Y 表示N或CH,
Q 表示H或CH3,
R1 表示H、F、Cl、Br、CN、CH3、CF3或OCH3,
R2 表示H、F或Cl,
R3 表示苯基、萘基、吡啶基、嘧啶基、喹啉基、异喹啉基、吲哚基、吲唑基、噻吩基、二氢异吲哚基或苯并咪唑基,其各自未被取代或被以下基团单-、双-或三取代:Hal、CN、NO2、A、(CR4)nOR4、(CR4)nN(R4)2、(CR4)nS(O)mR4、(CR4)nCON(R4)2、(CR4)nCOHet、(CR4)nSO2N(R4)2、(CR4)nSO2Het、(CR4)nN(R4)2、(CR4)nHet、O(CR4)nCOHet、(CR4)nO(CR4)nHet、(CR4)nN(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nN(R4)2、(CR4)nN(R4)COA、(CR4)nN(R4)COHet’、(CR4)nOcyc和/或(CR4)nCOOR4,
R4表示H或A’,
A 表示具有1-10个C-原子的无支链或支链的烷基,其中两个相邻碳原子可以形成双键,和/或一个或两个不相邻的CH-和/或CH2-基团可以被N-、O-和/或S-原子替换,且其中1-7个H-原子可以被R5替换,
或具有3-7个C原子的环状烷基,
A’ 表示具有1-6个C-原子的无支链或支链的烷基,其中一个或两个不相邻的CH-和/或CH2-基团可以被O-原子替换,
Cyc 表示环丁基、环戊基或环己基,其各自未被取代或被以下基团单-或双取代:A、Hal、OR4、N(R4)2、Het’、(CR4)nO(CR4)nHet’、CON(R4)2和/或=O,
R5 表示F、Cl或OH,
Het 表示吡咯烷基、吗啉基、哌啶基、哌嗪基、[1,4]-二氮杂环庚烷基、噁唑烷基、六氢-吡咯并[3,4-c]吡咯基、2-氧杂-6-氮杂-螺[3.4]辛基、2-氧杂-6-氮杂-螺[3.5]壬基、2-氧杂-7-氮杂-螺[3.5]壬基、2,5-二氧杂-8-氮杂-螺[3.5]壬基、氧杂环丁烷基、2-氧杂-5-氮杂-螺[3.4]辛基、2-氧杂-6-氮杂-螺[3.3]庚基、3-氮杂-双环[3.1.0]己基、2-氧杂-7-氮杂-螺[3.5]壬基、异噁唑烷基、氮杂环丁烷基、2,6-二氮杂-螺[3.4]辛基、六氢-吡咯并[3,4-b]吡咯基、四氢呋喃基或异噻唑烷基,其各自未被取代或被以下基团单-、双-或三取代:A、Hal、OR4、OCOA、COA、(CR4)nN(R4)2、(CR4)nHet’、(CR4)nO(CR4)nHet’、CON(R4)2、COHet’、(CR4)nS(O)mR4和/或=O,
Het’ 表示吡咯烷基、吗啉基、哌啶基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基、吡啶基、吡唑基或哌嗪基,其各自未被取代或被以下基团单-或双取代:A、Hal、OR4、N(R4)2和/或=O,
Hal 表示F、Cl、Br或I,
n 表示0、1、2或3,
m 表示0、1或2,
条件是,X1、X2、X3、X4中的仅一个或两个表示N,
和其药学上可接受的盐、互变异构体和立体异构体,包括它们的所有比率的混合物。
本发明还涉及这些化合物的光学活性形式(立体异构体)、对映异构体、外消旋物、非对映异构体以及水合物和溶剂化物。
此外,本发明涉及式I的化合物的药学上可接受的衍生物。
术语化合物的溶剂化物用于指惰性溶剂分子加合至化合物上,其因它们互相的吸引力而形成。溶剂化物为例如一水合物或二水合物或醇盐。
应当理解,本发明也涉及所述盐的溶剂化物。
术语药学上可接受的衍生物用于指例如根据本发明的化合物的盐和还有所谓的前药化合物。
如本文所使用且除非另有说明,术语“前药”意指式I的化合物的衍生物,其可在生物条件(体外或体内)下水解、氧化或以其它方式反应,以提供活性化合物、特别是式I的化合物。前药的实例包括、但不限于式I的化合物的衍生物和代谢产物,包括生物可水解的基团诸如生物可水解的酰胺、生物可水解的酯、生物可水解的氨基甲酸酯、生物可水解的碳酸酯、生物可水解的酰脲和生物可水解的磷酸酯类似物。在某些实施方案中,具有羧基官能团的化合物的前药是羧酸的低级烷基酯。羧酸酯通过使分子上存在的任何羧酸基团酯化而方便地形成。可通常使用众所周知的方法制备前药,所述方法诸如描述于Burger的MedicinalChemistry and Drug Discovery第六版(Donald J. Abraham主编, 2001, Wiley)和Design and Application of Prodrugs (H.Bundgaard主编, 1985, Harwood AcademicPublishers Gmfh)的那些。
表述“有效量”表示药物或药学上的活性成分的量,其在组织、系统、动物或人类中引起例如研究者或医师所寻找或期望的生物学或医学反应。
此外,表述“治疗有效量”表示与没有接受该量的相应受试者相比,具有下列结果的量:
改善地治疗、治愈、预防或消除疾病、综合征、状况、不适、病症或副作用,或以及减少疾病、不适或病症的发展。
表述“治疗有效量”还包括有效增加正常生理功能的量。
本发明还涉及式I的化合物的混合物、例如两种非对映异构体的混合物、例如比率为1:1、1:2、1:3、1:4、1:5、1:10、1:100或1:1000的两种非对映异构体的混合物的用途。
这些特别优选是立体异构的化合物的混合物。
“互变异构体”是指彼此处于平衡中的化合物的异构形式。异构形式的浓度将取决于化合物存在的环境,且可以根据例如化合物是固体还是在有机或水溶液中而不同。
本发明涉及式I的化合物及其盐,且涉及制备式I的化合物及其药学上可接受的盐、溶剂化物、互变异构体和立体异构体的方法,其特征在于,
a) 对于式I的化合物的制备,
其中
X1、X2、X3、X4 表示CH且
Y表示N,
使式II的化合物
其中R1、R2和Q具有权利要求1中所示的含义,
与式III的化合物反应,
其中R3具有权利要求1中所示的含义,
或者
b) 对于式I的化合物的制备,
其中
Y表示N,
使式IV的化合物
其中
且X1、X2、X3、X4、R1、R2和Q具有权利要求1中所示的含义,
与式V的化合物反应
其中R3具有权利要求1中所示的含义,
或者
c) 基团R3通过如下转化为另一基团R3:
i) 将羧基基团转化为酰胺,
ii) 将氨基基团酰化或烷基化,
或者
d) 通过用溶剂分解剂或氢解剂处理来将式I的化合物从其官能衍生物之一释放,
和/或
式I的碱或酸被转化为其盐之一。
在上文和下文中,基团X1、X2、X3、X4、R1、R2、R3、Q和Y具有关于式I所示的含义,除非明确地另外说明。
A表示烷基,其是无支链的(线性的)或支链的,且具有1、2、3、4、5、6、7、8、9或10个C原子。A优选地表示甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,此外还有戊基,1-、2-或3-甲基丁基,1,1-、1,2-或2,2-二甲基丙基,1-乙基丙基,己基,1-、2-、3-或4-甲基戊基,1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基,1-或2-乙基丁基,1-乙基-1-甲基丙基,1-乙基-2-甲基丙基,1,1,2-或1,2,2-三甲基丙基,进一步更优选地例如三氟甲基。
A非常特别优选地表示具有1、2、3、4、5或6个C原子的烷基,优选地表示甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、三氟甲基、五氟乙基或1,1,1-三氟乙基。
环状烷基优选表示环丙基、环丁基、环戊基或环己基。
此外,A优选地表示CH2OCH3、CH2CH2OH或CH2CH2OCH3。
A’表示烷基,这是无支链的(线性的)或支链的,且具有1、2、3、4、5或6个C原子。A’优选表示甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基。而且,A’优选表示CH2OCH3、CH2CH2OH或CH2CH2OCH3。
R1优选表示H、F、Cl、Br、CN、CH3、CF3或OCH3;尤其优选F或Cl。
R2优选表示H或F;尤其优选F。
R3优选表示苯基、吡啶基、嘧啶基、吲哚基、吲唑基、噻吩基、二氢异吲哚基或苯并咪唑基,其各自未被取代或被以下基团单-、双-或三取代:Hal、A、(CR4)nOR4、(CR4)nN(R4)2、(CR4)nS(O)mR4、(CR4)nCON(R4)2、(CR4)nCOHet、(CR4)nSO2Het、(CR4)nHet、O(CR4)nCOHet、(CR4)nO(CR4)nHet、(CR4)nN(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nN(R4)2、(CR4)nN(R4)COA、(CR4)nN(R4)COHet’、(CR4)nOCyc和/或(CR4)nCOOR4。
R3更优选表示苯基,其未被取代或被以下基团单-、双-或三取代:Hal、A、(CR4)nOR4、(CR4)nN(R4)2、(CR4)nS(O)mR4、(CR4)nCON(R4)2、(CR4)nCOHet、(CR4)nSO2Het、(CR4)nHet、O(CR4)nCOHet、(CR4)nO(CR4)nHet、(CR4)nN(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nN(R4)2、(CR4)nN(R4)COA、(CR4)nN(R4)COHet’、(CR4)nOCyc和/或(CR4)nCOOR4;
A优选表示具有1-10个C-原子的无支链或支链的烷基,
其中两个相邻碳原子可以形成双键,和/或一个或两个不相邻的CH-和/或CH2-基团可以被N-和/或O-原子替换,且其中1-7个H-原子可以被R5替换。
Het’优选表示吡咯烷基。
X1、X2、X3、X4 优选表示CH。
Y优选表示N。
贯穿本发明,出现多于一次的所有基团可以是相同或不同的,即彼此独立的。
式I的化合物可具有一个或多个手性中心,并且因此可以多种立体异构形式存在。式I涵盖所有这些形式。
因此,本发明具体而言涉及式I的化合物,其中所述基团中的至少一个具有上述优选含义之一。一些优选组的化合物可通过下述子式Ia至If及其药学上可接受的盐、互变异构体和立体异构体(包括它们的所有比率的混合物)表达,所述子式Ia至If与式I一致并且其中未更详细指定的基团具有对于式I所示的含义,但其中
在Ia中, R1表示H、F、Cl、Br、CN、CH3、CF3或OCH3,
R2 表示H或F;
在Ib中, R3表示苯基、吡啶基、嘧啶基、吲哚基、吲唑基、噻吩基、二氢异吲哚基或苯并咪唑基,其各自未被取代或被以下基团单-、双-或三取代:Hal、A、(CR4)nOR4、(CR4)nN(R4)2、(CR4)nS(O)mR4、(CR4)nCON(R4)2、(CR4)nCOHet、(CR4)nSO2Het、(CR4)nHet、O(CR4)nCOHet、(CR4)nO(CR4)nHet、(CR4)nN(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nN(R4)2、(CR4)nN(R4)COA、(CR4)nN(R4)COHet’、(CR4)nOCyc和/或(CR4)nCOOR4;
在Ic中, A 表示具有1-10个C-原子的无支链或支链的烷基,其中两个相邻碳原子可以形成双键,和/或一个或两个不相邻的CH-和/或CH2-基团可以被N-和/或O-原子替换,且其中1-7个H-原子可以被R5替换;
在Id中, Het’表示吡咯烷基;
在Ie中, X1、X2、X3、X4 各自彼此独立地表示CH或N,
Y 表示N或CH,
Q 表示H或CH3,
R1 表示H、F、Cl、Br、CN、CH3、CF3或OCH3,
R2 表示H或F,
R3 表示苯基、吡啶基、嘧啶基、吲哚基、吲唑基、噻吩基、二氢异吲哚基或苯并咪唑基,其各自未被取代或被以下基团单-、双-或三取代:Hal、A、(CR4)nOR4、(CR4)nN(R4)2、(CR4)nS(O)mR4、(CR4)nCON(R4)2、(CR4)nCOHet、(CR4)nSO2Het、(CR4)nHet、O(CR4)nCOHet、(CR4)nO(CR4)nHet、(CR4)nN(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nN(R4)2、(CR4)nN(R4)COA、(CR4)nN(R4)COHet’、(CR4)nOCyc和/或(CR4)nCOOR4,
R4 表示H或A’,
A 表示具有1-10个C-原子的无支链或支链的烷基,其中两个相邻碳原子可以形成双键,和/或一个或两个不相邻的CH-和/或CH2-基团可以被N-和/或O-原子替换,且其中1-7个H-原子可以被R5替换,
Cyc 表示环丁基、环戊基或环己基,其各自未被取代或被以下基团单-或双取代:A、Hal、OR4、N(R4)2、Het’、(CR4)nO(CR4)nHet’、CON(R4)2和/或=O,
A’ 表示具有1-6个C-原子的无支链或支链的烷基,其中一个或两个不相邻的CH-和/或CH2-基团可以被O-原子替换,
R5 表示F、Cl或OH,
Het 表示吡咯烷基、吗啉基、哌啶基、哌嗪基、[1,4]-二氮杂环庚烷基、噁唑烷基、六氢-吡咯并[3,4-c]吡咯基、2-氧杂-6-氮杂-螺[3.4]辛基、2-氧杂-6-氮杂-螺[3.5]壬基、2-氧杂-7-氮杂-螺[3.5]壬基、2,5-二氧杂-8-氮杂-螺[3.5]壬基、氧杂环丁烷基、2-氧杂-5-氮杂-螺[3.4]辛基、2-氧杂-6-氮杂-螺[3.3]庚基、3-氮杂-双环[3.1.0]己基、2-氧杂-7-氮杂-螺[3.5]壬基、异噁唑烷基、氮杂环丁烷基、2,6-二氮杂-螺[3.4]辛基、六氢-吡咯并[3,4-b]吡咯基、四氢呋喃基或异噻唑烷基,其各自未被取代或被以下基团单-、双-或三取代:A、Hal、OR4、OCOA、COA、(CR4)nN(R4)2、(CR4)nHet’、(CR4)nO(CR4)nHet’、CON(R4)2、COHet’、(CR4)nS(O)mR4和/或=O,
Het’ 表示吡咯烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基、吡啶基或吡唑基,
Hal 表示F、Cl、Br或I,
n 表示0、1、2或3,
m 表示0、1或2,
在If中, X1、X2、X3、X4 表示CH,
Y 表示N,
Q 表示H或CH3,
R1 表示H、F、Cl、Br、CN、CH3、CF3或OCH3,
R2 表示H或F,
R3 表示苯基,其未被取代或被以下基团单-、双-或三取代:Hal、A、(CR4)nOR4、(CR4)nN(R4)2、(CR4)nS(O)mR4、(CR4)nCON(R4)2、(CR4)nCOHet、(CR4)nSO2Het、(CR4)nHet、O(CR4)nCOHet、(CR4)nO(CR4)nHet、(CR4)nN(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nN(R4)2、(CR4)nN(R4)COA、(CR4)nN(R4)COHet’、(CR4)nOCyc和/或(CR4)nCOOR4,
R4 表示H或A’,
A 表示具有1-10个C-原子的无支链或支链的烷基,其中两个相邻碳原子可以形成双键,和/或一个或两个不相邻的CH-和/或CH2-基团可以被N-和/或O-原子替换,且其中1-7个H-原子可以被R5替换,
Cyc 表示环丁基、环戊基或环己基,其各自未被取代或被以下基团单-或双取代:A、Hal、OR4、N(R4)2、Het’、(CR4)nO(CR4)nHet’、CON(R4)2和/或=O,
A’ 表示具有1-6个C-原子的无支链或支链的烷基,其中一个或两个不相邻的CH-和/或CH2-基团可以被O-原子替换,
R5 表示F、Cl或OH,
Het 表示吡咯烷基、吗啉基、哌啶基、哌嗪基、[1,4]-二氮杂环庚烷基、噁唑烷基、六氢-吡咯并[3,4-c]吡咯基、2-氧杂-6-氮杂-螺[3.4]辛基、2-氧杂-6-氮杂-螺[3.5]壬基、2-氧杂-7-氮杂-螺[3.5]壬基、2,5-二氧杂-8-氮杂-螺[3.5]壬基、氧杂环丁烷基、2-氧杂-5-氮杂-螺[3.4]辛基、2-氧杂-6-氮杂-螺[3.3]庚基、3-氮杂-双环[3.1.0]己基、2-氧杂-7-氮杂-螺[3.5]壬基、异噁唑烷基、氮杂环丁烷基、2,6-二氮杂-螺[3.4]辛基、六氢-吡咯并[3,4-b]吡咯基、四氢呋喃基或异噻唑烷基,其各自未被取代或被以下基团单-、双-或三取代:A、Hal、OR4、OCOA、COA、(CR4)nN(R4)2、(CR4)nHet’、(CR4)nO(CR4)nHet’、CON(R4)2、COHet’、(CR4)nS(O)mR4和/或=O,
Het’ 表示吡咯烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基、吡啶基或吡唑基,
Hal 表示F、Cl、Br或I,
n 表示0、1、2或3,
m 表示0、1或2,
和其药学上可接受的盐、互变异构体和立体异构体,包括其所有比率的混合物。
此外,式I的化合物以及用于其制备的起始原料通过本身已知的方法制备,如在文献(例如在标准著作中,诸如Houben-Weyl, Methoden der organischen Chemie [Methodsof Organic Chemistry], Georg-Thieme-Verlag, Stuttgart)中所述,精确而言,在已知且适合于所述反应的反应条件下。在此也可以使用在此未更详细提及的本身已知的变体形式。
式II和III的起始化合物通常是已知的。然而如果它们是新型的,则它们可通过本身已知的方法制备。
可优选通过使式II的化合物与式III的化合物反应获得式I的化合物。该反应被称为“点击-反应”并且通常在惰性溶剂中、优选在CuSO4和抗坏血酸钠或异抗坏血酸钠存在的情况下进行。
根据所用的条件,反应时间是在几分钟和14天之间,反应温度是在约0°和140°之间,通常在20°和130°之间,特别是在约80°和约120°之间。
合适的惰性溶剂的实例是烃类,诸如己烷、石油醚、苯、甲苯或二甲苯;氯化烃类,诸如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷;醇,诸如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚,诸如乙醚、二异丙醚、四氢呋喃(THF)或二噁烷;二醇醚,诸如乙二醇单甲醚或乙二醇单乙醚、乙二醇二甲醚(diglyme);酮,诸如丙酮或丁酮;酰胺,诸如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈,诸如乙腈;亚砜,诸如二甲亚砜(DMSO);二硫化碳;羧酸,诸如甲酸或乙酸;硝基化合物,诸如硝基甲烷或硝基苯;酯类,诸如乙酸乙酯,或所述溶剂的混合物。
特别优选的是DMF。
式IV和V的起始化合物通常是已知的。然而如果它们是新型的,则它们可通过本身已知的方法制备。
可优选通过使式IV的化合物与式V的化合物反应来获得式I的化合物。
反应通常在酸结合剂(优选有机碱,诸如DIPEA、三乙胺、二甲基苯胺、吡啶或喹啉)存在的情况下实施。
而且,反应通常在[二甲基氨基-([1,2,3]三唑并[4,5-b]吡啶-3-基氧基)-亚甲基]-二甲基-六氟磷酸铵(HATU)存在的情况下实施。
根据所用的条件,反应时间是在几分钟和14天之间,反应温度是在约-30°和140°之间,通常在-10°和90°之间,特别是在约0°和约70°之间。
合适的惰性溶剂的实例是烃类,诸如己烷、石油醚、苯、甲苯或二甲苯;氯化烃类,诸如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷;醇,诸如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚,诸如乙醚、二异丙醚、四氢呋喃(THF)或二噁烷;二醇醚,诸如乙二醇单甲醚或乙二醇单乙醚、乙二醇二甲醚(diglyme);酮,诸如丙酮或丁酮;酰胺,诸如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈,诸如乙腈;亚砜,诸如二甲亚砜(DMSO);二硫化碳;羧酸,诸如甲酸或乙酸;硝基化合物,诸如硝基甲烷或硝基苯;酯类,诸如乙酸乙酯,或所述溶剂的混合物。
特别优选的是乙腈、二氯甲烷和/或DMF。
或者,反应在改良的Frielaender喹诺酮合成条件下,用羧酸酐诸如乙酸酐作为溶剂和缩合剂且用酸结合剂诸如三甲胺或DIPEA实施。
此外可以将式I的化合物转化为另一种式I的化合物,例如通过将硝基基团还原为氨基基团(例如通过在雷尼镍或Pd/碳上在惰性溶剂诸如甲醇或乙醇中氢化)。
此外,游离氨基基团可以使用酰氯或酸酐以常规方式酰化,或者使用未取代或取代的烷基卤化物烷基化,有利地在惰性溶剂诸如二氯甲烷或THF中,和/或在碱诸如三乙胺或吡啶的存在下,在-60至+30°之间的温度下进行。
烷基化也可以在还原烷基化条件(诸如使用HCHO和NaBH3CN)下进行。
式I的化合物还可以通过溶剂分解、特别是水解或通过氢解从它们的官能衍生物中释放它们来获得。
用于溶剂分解或氢解的优选起始原料是含有相应的被保护的氨基和/或羟基基团而不是一个或多个游离氨基和/或羟基基团的那些,优选携带氨基保护基团而不是与N原子键合的H原子的那些,例如符合式I、但含有NHR’基团(其中R’是氨基保护基团,例如BOC或CBZ)而不是NH2基团的那些。
此外优选的是携带羟基-保护基团而不是羟基基团的H原子的起始原料,例如符合式I、但含有R”O-苯基基团(其中R”是羟基保护基团)而不是羟基-苯基基团的那些。
也可能在起始原料的分子中存在多个相同或不同的被保护的氨基和/或羟基基团。如果存在的保护基团彼此不同,则它们可以在许多情况下选择性地裂解。
术语“氨基保护基团”通常是已知的,并且涉及适合于保护(封闭)氨基基团以防化学反应、但在分子中其它地方实施期望的化学反应之后易于移除的基团。此类基团的典型尤其是未取代或取代的酰基、芳基、芳烷氧基甲基或芳烷基基团。由于氨基保护基团在期望的反应(或反应序列)后被移除,所以它们的类型和大小此外并不重要;然而,优选具有1-20个、特别是1-8个碳原子的那些。术语“酰基基团”应当以与本发明的方法有关的最广泛的含义来理解。其包括由脂族、芳脂族、芳族或杂环羧酸或磺酸衍生的酰基基团,特别是烷氧基羰基、芳基氧基羰基和特别是芳烷氧基羰基基团。此类酰基基团的实例是烷酰基,诸如乙酰基、丙酰基和丁酰基;芳烷酰基,诸如苯基乙酰基;芳酰基,诸如苯甲酰基和甲苯基;芳基氧基烷酰基,诸如POA;烷氧基羰基,诸如甲氧基羰基、乙氧基羰基、2,2,2-三氯乙氧基羰基、BOC和2-碘乙氧基羰基;芳烷氧基羰基,诸如CBZ(“羰基苯氧基”)、4-甲氧基苄氧基羰基和FMOC;和芳基磺酰基,诸如Mtr、Pbf和Pmc。优选的氨基保护基团是BOC和Mtr,还有CBZ、Fmoc、苄基和乙酰基。
术语“羟基保护基团”同样通常是已知的,并且涉及适合于保护羟基基团以防化学反应、但在分子中其它地方实施期望的化学反应之后易于移除的基团。此类基团的典型是上面提及的未取代或取代的芳基、芳烷基或酰基基团,此外还有烷基基团。羟基保护基团的性质和大小并不重要,因为它们在期望的化学反应或反应序列后被再次移除;优选具有1-20个、特别是1-10个碳原子的基团。羟基保护基团的实例尤其是叔丁氧基羰基、苄基、对硝基苯甲酰基、对甲苯磺酰基、叔丁基和乙酰基,其中苄基和叔丁基是特别优选的。
式I的化合物从其官能衍生物释放 – 这取决于所用的保护基团 - 例如使用强酸,有利地使用TFA或高氯酸,而且还使用其它强无机酸,诸如盐酸或硫酸,强有机羧酸,诸如三氯乙酸,或磺酸类,诸如苯-或对甲苯磺酸。可能存在额外的惰性溶剂,但并不总是必需的。合适的惰性溶剂优选为有机的,例如羧酸,诸如乙酸,醚,诸如四氢呋喃或二氧杂环己烷,酰胺,诸如DMF,卤代烃,诸如二氯甲烷,此外还有醇,诸如甲醇、乙醇或异丙醇,和水。上面提及的溶剂的混合物也是合适的。优选过量使用TFA,而不添加另外的溶剂,并且高氯酸优选以乙酸与70%高氯酸以比率9:1的混合物的形式使用。用于裂解的反应温度有利地在约0和约50°之间,优选在15和30°之间(室温)。
BOC、OBut、Pbf、Pmc和Mtr基团可以例如优选使用TFA/二氯甲烷或使用近似3-5NHCl/二氧杂环己烷在15-30°下进行裂解,并且FMOC基团可以使用二甲胺、二乙胺或哌啶于DMF中的近似5至50%溶液在15-30°下进行裂解。
氢解可移除的保护基团(例如CBZ或苄基)可以被裂解,例如通过在催化剂(例如贵金属催化剂,诸如钯,有利地在支持物诸如碳上)存在的情况下用氢处理。此处合适的溶剂是上面所示的那些,特别是例如醇,诸如甲醇或乙醇,或酰胺,诸如DMF。氢解通常在约0和100°之间的温度和约1和200巴之间的压力,优选在20-30°和1-10巴实施。CBZ基团的氢解例如在甲醇中的5至10% Pd/C上或使用甲醇/ DMF中的Pd/C上的甲酸铵(而不是氢)在20-30°下完全成功。
此外,式I的化合物可优选通过经由将羧基基团转化为酰胺而将基团R3转化为另一基团R3而获得。
反应通常在偶联剂(诸如HATU)和酸结合剂(优选有机碱,诸如DIPEA、三乙胺、二甲基苯胺、吡啶或喹啉)存在的情况下实施。
添加碱金属或碱土金属氢氧化物、碱金属或碱土金属(优选钾、钠、钙或铯) 的碳酸盐或碳酸氢盐或弱酸的另一种盐也可以是有利的。
根据所用的条件,反应时间是在几分钟和14天之间,反应温度是在约-30°和140°之间,通常在-10°和90°之间,特别是在约0°和约70°之间。
合适的惰性溶剂的实例是烃类,诸如己烷、石油醚、苯、甲苯或二甲苯;氯化烃类,诸如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷;醇,诸如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚,诸如乙醚、二异丙醚、四氢呋喃(THF)或二噁烷;二醇醚,诸如乙二醇单甲醚或乙二醇单乙醚、乙二醇二甲醚(diglyme);酮,诸如丙酮或丁酮;酰胺,诸如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈,诸如乙腈;亚砜,诸如二甲亚砜(DMSO);二硫化碳;羧酸,诸如甲酸或乙酸;硝基化合物,诸如硝基甲烷或硝基苯;酯类,诸如乙酸乙酯,或所述溶剂的混合物。
特别优选的是乙腈、二氯甲烷和/或DMF。
药用盐和其它形式
所述根据本发明的化合物可以以其最终的非盐形式使用。另一方面,本发明还涵盖这些化合物以其药学上可接受的盐形式的使用,所述药学上可接受的盐可以通过本领域已知的操作由各种有机和无机酸和碱衍生得到。式I的化合物的药学上可接受的盐形式大部分通过常规方法制备。如果式I的化合物含有羧基,则其合适的盐之一可通过使该化合物与合适的碱反应以得到相应的碱加成盐来形成。此类碱是例如碱金属氢氧化物,包括氢氧化钾、氢氧化钠和氢氧化锂;碱土金属氢氧化物,诸如氢氧化钡和氢氧化钙;碱金属醇盐,例如乙醇钾和丙醇钠;和各种有机碱,诸如哌啶、二乙醇胺和N-甲基谷氨酰胺。同样包括式I的化合物的铝盐。在某些式I的化合物的情况下,可以通过用药学上可接受的有机和无机酸处理这些化合物来形成酸加成盐,所述酸诸如卤化氢,诸如氯化氢、溴化氢或碘化氢;其它无机酸及其相应的盐,诸如硫酸盐、硝酸盐或磷酸盐等;和烷基-和单芳基-磺酸盐,诸如乙磺酸盐、甲苯磺酸盐和苯磺酸盐;和其它有机酸及其相应的盐,诸如乙酸盐、三氟乙酸盐、酒石酸盐、马来酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐等。因此,式I的化合物的药学上可接受的酸加成盐包括以下盐:乙酸盐、己二酸盐、藻酸盐、精氨酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐(苯基磺酸盐)、硫酸氢盐、亚硫酸氢盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐、辛酸盐、氯化物、氯苯甲酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、磷酸二氢盐、二硝基苯甲酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、甲酸盐、半乳糖二酸盐(galacterate)(得自粘酸)、半乳糖醛酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、甘油磷酸盐、半琥珀酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、碘化物、羟乙基磺酸盐、异丁酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲磺酸盐、甲基苯甲酸盐、磷酸一氢盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、palmoate、果胶酸盐(pectinate)、过硫酸盐,苯基乙酸盐、3-苯基丙酸盐、磷酸盐、膦酸盐、邻苯二甲酸盐,但这不旨在代表限于此。
此外,根据本发明的化合物的碱式盐包括铝盐、铵盐、钙盐、铜盐、铁(III)盐、铁(II)盐、锂盐、镁盐、锰(III)盐、锰(II)盐、钾盐、钠盐和锌盐,但这不旨在代表限于此。在上述盐中,优选铵盐;碱金属盐钠盐和钾盐,以及碱土金属盐钙盐和镁盐。衍生自药学上可接受的有机无毒碱的式I的化合物的盐包括以下物质的盐:伯、仲和叔胺、被取代的胺,还包括天然存在的被取代的胺、环状胺和碱性离子交换树脂,例如精氨酸、甜菜碱、咖啡因、氯普鲁卡因、胆碱、N,N′-二苄基乙二胺(benzathine)、二环己基胺、二乙醇胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡糖、组氨酸、哈胺(hydrabamine)、异丙胺、利多卡因、赖氨酸、葡甲胺、N-甲基-D-葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤类化合物、可可碱、三乙醇胺、三乙胺、三甲胺、三丙胺和三(羟基甲基)甲胺(氨基丁三醇),但这不旨在代表限于此。
可以用诸如以下试剂将含有碱性含氮基团的本发明的化合物季铵化(quaternised):(C1-C4)烷基卤化物,例如甲基、乙基、异丙基和叔丁基的氯化物、溴化物和碘化物;硫酸二(C1-C4)烷基酯,例如硫酸二甲酯、硫酸二乙酯和硫酸二戊酯;(C10-C18)烷基卤化物,例如癸基、十二烷基、月桂基、肉豆蔻基和硬脂基(stearyl)的氯化物、溴化物和碘化物;以及芳基(C1-C4)烷基卤化物,例如苄基氯和苯乙基溴。可以用此类盐来制备水溶性和油溶性的根据本发明的化合物。
优选的上述药用盐包括乙酸盐、三氟乙酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、葡糖酸盐、半琥珀酸盐、马尿酸盐、盐酸盐、氢溴酸盐、羟乙基磺酸盐、扁桃酸盐、葡甲胺、硝酸盐、油酸盐、膦酸盐、新戊酸盐、磷酸钠、硬脂酸盐、硫酸盐、磺基水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和氨基丁三醇,但这不旨在代表限于此。
特别优选的是,盐酸盐、二盐酸盐、氢溴酸盐、马来酸盐、甲磺酸盐、磷酸盐、硫酸盐和琥珀酸盐。
如下制备式I的碱性化合物的酸加成盐:通过将游离碱形式与足够量的期望的酸接触,从而以常规方式形成盐。可以通过以常规方式将盐形式与碱接触且分离出游离碱而再生游离碱。就某些物理性质而言,游离碱形式在某些方面与其相应的盐形式不同,诸如在极性溶剂中的溶解度方面;然而,对于本发明的目的而言,盐在其它方面对应于其各自的游离碱形式。
如上所述,式I的化合物的药学上可接受的碱加成盐用金属类或胺类化合物诸如碱金属和碱土金属或有机胺形成。优选的金属是钠、钾、镁和钙。优选的有机胺是N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基-D-葡萄糖胺和普鲁卡因。
如下制备根据本发明的酸性化合物的碱加成盐:通过以常规方式将游离酸形式与足够量的所需的碱接触,从而形成盐。可以通过以常规方式将盐形式与酸接触且分离出游离酸而再生游离酸。就某些物理性质而言,游离酸形式在某些方面与其相应的盐形式不同,诸如在极性溶剂中的溶解度方面;然而,对于本发明的目的而言,盐在其它方面对应于其各自的游离酸形式。
如果根据本发明的化合物含有多于一个能够形成此类药学上可接受的盐的基团,则本发明还涵盖多重盐。典型的多重盐形式包括例如酒石酸氢盐、二乙酸盐、二富马酸盐、二葡甲胺、二磷酸盐、二钠盐和三盐酸盐,但这不旨在代表限于此。
关于上文所述,可见在本文关系中的表述“药学上可接受的盐”用于指包含呈其盐之一形式的式I的化合物的活性成分,特别是如果与游离形式的活性成分或较早使用的活性成分的任何其它盐形式相比,该盐形式赋予活性成分改进的药代动力学性质的话。活性成分的药学上可接受的盐形式还可首次为该活性成分提供期望的药代动力学性质(其较早没有所述药代动力学性质),并且关于其在机体内的治疗功效而言,甚至可对该活性成分的药效动力学具有积极影响。
同位素
此外,式I的化合物意欲包括其同位素-标记的形式。除了以下事实以外,式I的化合物的同位素-标记的形式与所述化合物是相同的:所述化合物的一个或多个原子被原子质量或质量数与自然界中常见的所述原子的原子质量或质量数不同的一个或多个原子替换。易于商业购得且可以通过众所周知的方法引入式I的化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,例如分别为2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36CI。含有一个或多个上述同位素和/或其它原子的其它同位素的式I的化合物、其前药、或其任一种的药学上可接受的盐意欲为本发明的一部分。同位素-标记的式I的化合物可以以多种有利的方式使用。例如,同位素-标记的式I的化合物(其中例如已经掺入放射性同位素诸如3H或14C)适合用于药物和/或底物组织分布测定。由于简单的制备和优良的可检测性,特别优选这些放射性同位素,即氚(3H)和碳-14 (14C)。在式I的化合物中引入较重的同位素例如氘(2H)具有治疗优点,这归因于该同位素-标记的化合物的较高代谢稳定性。较高代谢稳定性直接转化为增加的体内半衰期或更低的剂量,其在大多数情况下将代表本发明的优选实施方案。通常,通过实施在合成方案及相关描述中、在实施例部分中和在本文的制备部分中公开的程序,用易得的同位素-标记的反应物替换非同位素标记的反应物,可以制备同位素-标记的式I的化合物。
为了通过初级动力学同位素效应操作所述化合物的氧化代谢的目的,还可以将氘(2H)引入式I的化合物中。所述初级动力学同位素效应是由同位素核的交换而引起的化学反应速率的变化,所述变化进而由在该同位素交换后共价键形成所需的基态能的变化引起。较重同位素的交换经常导致化学键的基态能的降低,因此使限速键断裂的速率降低。如果键断裂发生在沿多产物反应的坐标的鞍点区或其附近,则可以显著改变产物分布比率。为了进行解释:如果氘与不可交换位置处的碳原子键合,则kM/kD = 2-7的速率差异是典型的。如果将该速率差异成功地应用于易于氧化的式I的化合物,则可显著地改变所述化合物的体内概况,且导致改善的药代动力学特性。
在发现和开发治疗剂时,本领域技术人员试图优化药代动力学参数,同时保持期望的体外特性。合理地假定,许多具有差药代动力学概况的化合物易于氧化代谢。目前可利用的体外肝微粒体测定提供关于此类氧化代谢的过程的有价值的信息,所述信息进而允许合理设计通过对抗此类氧化代谢而具有改善的稳定性的氘化的式I的化合物。由此获得式I的化合物的药代动力学概况的显著改善,并且可以在以下方面定量地表示:体内半衰期(t1/2)、最大治疗效果时的浓度(Cmax)、剂量响应曲线下面积(AUC)以及F的增加;以及降低的清除率、剂量和材料成本。
以下意欲说明上述内容:将具有氧化代谢的多个潜在攻击位点(例如苄基上的氢原子和与氮原子键合的氢原子)的式I的化合物制备为一系列类似物,其中氢原子的各种组合被氘原子替换,使得这些氢原子中的一些、大部分或全部已经被氘原子替代。半衰期测定能够有利且精确地确定已经改善的氧化代谢抗性的改善的程度。以该方式,确定了作为此类氘-氢交换的结果,母体化合物的半衰期可以延长最多达100%。
式I的化合物中的氘-氢交换也可以用于实现有利地修饰起始化合物的代谢物谱,以便减少或消除不期望的毒性代谢物。例如,如果毒性代谢物通过氧化性的碳-氢(C-H)键裂解而产生,则可以合理地假定,氘化的类似物将大大减少或消除不希望的代谢物的产生,即使特定氧化不是定速步骤。关于氘-氢交换的现有技术状态的其它信息,可以参见例如,Hanzlik等人, J. Org. Chem. 55, 3992-3997, 1990, Reider等人, J. Org. Chem. 52,3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette等人,Biochemistry 33(10) 2927-2937, 1994, 和Jarman等人. Carcinogenesis 16(4), 683-688, 1993。
此外,本发明涉及药物,其包含至少一种式I的化合物和/或其药学上可接受的盐、溶剂化物和立体异构体(包括它们的所有比率的混合物)和任选地赋形剂和/或辅剂。
药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式给药。此单位可包含例如0.5 mg-1 g、优选1 mg-700 mg、尤其优选5 mg-100 mg的根据本发明的化合物,这取决于所治疗的状况、给药方法以及患者的年龄、体重和状况,或者药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式给药。优选的剂量单位制剂是包含活性成分的如上所示的每日剂量或部分剂量或者其对应级分的那些。此外,此类药物制剂可以使用药学领域中通常已知的方法来制备。
药物制剂可适用于经由任何期望的合适方法给药,例如通过口服(包括经颊或舌下)、直肠、经鼻、局部(包括经颊、舌下或透皮)、阴道或肠胃外(包括皮下、肌内、静脉内或真皮内)方法。此类制剂可使用药学领域中已知的所有方法制备,例如通过将活性成分与赋形剂(诸赋形剂)或辅剂(诸辅剂)组合。
适于口服给药的药物制剂可以作为单独的单位进行给药,所述单独的单位诸如例如胶囊或片剂;粉末或颗粒;在水性或非水性液体中的溶液或悬浮液;可食用的泡沫或泡沫食物;或水包油型液体乳剂或油包水型液体乳剂。
因此,例如,在以片剂或胶囊形式口服给药的情况下,可以将活性成分组分与口服无毒的和药学上可接受的惰性赋形剂诸如例如乙醇、甘油、水等组合。粉末通过将化合物粉碎至适当细的大小且将其与以相似方式粉碎的药用赋形剂诸如例如可食用的碳水化合物诸如例如淀粉或甘露醇混合来制备。同样可以存在矫味剂、防腐剂、分散剂和染料。
通过如上所述制备粉末混合物且用其填充成型的明胶壳来生产胶囊。在填充操作之前,可以向粉末混合物中添加固体形式的助流剂和润滑剂,诸如例如高度分散的硅酸、滑石、硬脂酸镁、硬脂酸钙或聚乙二醇。同样可以添加崩解剂或增溶剂诸如例如琼脂-琼脂、碳酸钙或碳酸钠以改善胶囊被服用后的药物的利用度。
此外,如果需要或必要,同样可以向混合物中掺入合适的粘合剂、润滑剂和崩解剂以及染料。合适的粘合剂包括淀粉、明胶、天然糖类诸如例如葡萄糖或β-乳糖、由玉米制备的甜味剂、天然和合成橡胶诸如例如阿拉伯胶、西黄蓍胶或藻酸钠、羧甲基纤维素、聚乙二醇、蜡等。这些剂型中所用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂非限制性地包括淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。如下配制片剂:例如制备粉末混合物,将该混合物制粒或干压,添加润滑剂和崩解剂且将整个混合物压成片剂。如下制备粉末混合物:通过将以合适的方式粉碎的化合物与上述稀释剂或基质混合,且任选地与粘合剂诸如例如羧甲基纤维素、藻酸盐、明胶或聚乙烯吡咯烷酮、溶出阻滞剂诸如例如石蜡、吸收促进剂诸如例如季盐和/或吸收剂诸如例如膨润土、高岭土或磷酸二钙混合。可以通过用粘合剂诸如例如糖浆、淀粉糊、acadia胶浆或者纤维素或聚合物材料的溶液润湿且将其压过筛而将粉末混合物制粒。作为制粒的一个替代方案,可以使粉末混合物通过压片机,得到形状不均匀的块状物,将其破碎以形成颗粒。可通过添加硬脂酸、硬脂酸盐、滑石或矿物油对颗粒进行润滑以防止粘附于片剂铸模。然后,将被润滑的混合物压成片剂。也可以将根据本发明的化合物与自由流动的惰性赋形剂组合,然后在不实施制粒或干压步骤的情况下直接压成片剂。可以存在由虫胶密封层、糖或聚合物物质层和蜡的光泽层组成的透明或不透明的保护层。可以向这些包衣中添加染料以便能够区别不同的剂量单位。
口服液体诸如例如溶液、糖浆和酏剂可以以剂量单位形式制备,使得给定量包含预定量的化合物。糖浆可以通过将化合物与合适矫味剂溶解于水性溶液中来制备,而酏剂使用无毒的醇性媒介物来制备。悬浮液可以通过将化合物分散于无毒媒介物中来配制。同样可以添加增溶剂和乳化剂诸如例如乙氧基化的异硬脂醇和聚氧乙烯山梨醇醚类化合物、防腐剂、矫味添加剂诸如例如薄荷油或天然甜味剂或糖精或其它人工甜味剂等。
如果需要,可以将用于口服给药的剂量单位制剂包封于微囊中。也可以以释放被延长或延迟的方式来制备制剂,诸如例如通过将微粒材料包衣或包埋于聚合物、蜡等中来制备制剂。
式I的化合物及其药用盐、互变异构体和立体异构体也可以以脂质体递送系统诸如例如小单层囊泡、大单层囊泡和多层囊泡的形式进行给药。可以从各种磷脂诸如例如胆固醇、硬脂胺或磷脂酰胆碱形成脂质体。
式I的化合物及其盐、互变异构体和立体异构体也可以用单克隆抗体作为独立载体而进行递送,其中所述化合物分子与所述单克隆抗体偶联。也可以将化合物偶联至作为靶向药物载体的可溶性聚合物。此类聚合物可涵盖聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰氨基苯酚(polyhydroxypropylmethacrylamidophenol)、聚羟乙基天冬酰氨基苯酚或聚氧化乙烯聚赖氨酸(被棕榈酰基取代)。还可以将化合物偶联至一类适于实现药物控释的生物可降解聚合物,例如聚乳酸、聚-ε-己内酯、聚羟基丁酸、聚原酸酯类化合物、聚缩醛类化合物、聚二羟基吡喃类化合物、聚氰基丙烯酸酯类化合物和水凝胶的交联或两亲性嵌段共聚物。
适合于经皮给药的药物制剂可以作为与受体的表皮长期紧密接触的独立硬膏剂给药。因此,例如,可以通过离子电渗疗法使活性成分从硬膏剂递送,如PharmaceuticalResearch, 3(6), 318 (1986)中的通用术语中所述的那样。
适合于局部给药的药物化合物可以被配制成软膏剂、乳膏剂、混悬剂、洗剂、粉末、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂或油。
对于眼或其它外部组织例如口和皮肤的治疗,制剂优选地作为局部用软膏剂或乳膏剂施用。在配制以得到软膏剂的情况下,可以将活性成分与石蜡的或水可混溶的乳膏基质一起利用。或者,可以用水包油型乳膏基质或油包水型基质将活性成分配制成乳膏剂。
适合于局部施用于眼的药物制剂包括滴眼剂,其中将活性成分溶解或混悬于合适的载体、特别是水性溶剂中。
适合于在口中局部施用的药物制剂涵盖锭剂、软锭剂和漱口剂。
适合于直肠给药的药物制剂可以以栓剂或灌肠剂的形式给药。
其中载体物质是固体的适合于经鼻给药的药物制剂包含具有例如在20-500微米范围内的粒径的粗粉末,其以吸入鼻烟(snuff)的方式给药,即经由鼻道从靠近鼻的含粉末容器迅速吸入。用于以液体作为载体物质、作为鼻喷雾剂或滴鼻剂给药的合适制剂涵盖活性成分在水或油中的溶液。
适合于通过吸入给药的药物制剂涵盖细微粒粉或雾,其可通过各种类型的具有气雾剂的加压分配器、喷雾器或吹入器来生成。
适合于阴道给药的药物制剂可以作为子宫托、卫生棉、乳膏剂、凝胶剂、糊剂、泡沫或喷雾制剂来给药。
适合于肠胃外给药的药物制剂包括水性的和非水性的无菌注射溶液,其包含抗氧化剂、缓冲剂、抑菌剂和溶质,借此使得制剂与待治疗的受体的血液等张;以及水性的和非水性的无菌悬浮液,其可以包含混悬介质和增稠剂。该制剂可以在单剂量或多剂量容器、例如密封的安瓿和小瓶中给药,且以冷冻干燥(冻干)状态储存,使得仅需要就在临用前才添加无菌载体液体例如注射用水。根据处方制备的注射溶液和悬浮液可以从无菌粉末、颗粒和片剂制备。
不言而喻,除了上面特别提及的组分以外,该制剂还可以包含就该特定类型的制剂而言在本领域中常用的其它试剂;因此,例如,适合于口服给药的制剂可以包含矫味剂。
式I的化合物的治疗有效量取决于许多因素,包括例如动物的年龄和体重、需要治疗的准确病况及其严重度、制剂的性质和给药方法,且最终由主治医生或兽医来决定。然而,根据本发明的化合物的有效量通常是在0.1-100 mg/kg受体(哺乳动物)体重/天的范围内,特别是通常在1-10 mg/kg体重/天的范围内。因此,对于体重为70kg的成年哺乳动物而言,每天的实际量通常在70-700mg之间,其中该量可以作为每天的单次剂量给药,或者通常在每天的一系列分份剂量(诸如例如,2、3、4、5或6份)中给药,使得总日剂量相同。其盐或溶剂化物或生理学官能衍生物的有效量可以被确定为根据本发明的化合物本身的有效量的分数。可以假定,相似剂量适合于治疗上述的其它病症。
该类型的联合治疗可借助于同时、连续或分别分配该治疗的各组分来实现。该类型的组合产品采用根据本发明的化合物。
此外,本发明涉及药物,其包含至少一种式I的化合物和/或其药学上可接受的盐、互变异构体和立体异构体(包括它们的所有比率的混合物)以及至少一种另外的药物活性成分。
本发明还涉及套盒(试剂盒),其由如下的单独包装组成:
(a) 有效量的式I的化合物和/或其药学上可接受的盐、互变异构体和立体异构体,包括它们的所有比率的混合物,
和
(b) 有效量的另外的药物活性成分。
该套盒包含合适的容器,诸如盒、单个瓶、袋或安瓿。该套盒可以例如包含分开的安瓿,其各自含有有效量的式I的化合物和/或其药学上可接受的盐、互变异构体和立体异构体,包括它们的所有比率的混合物,
和有效量的呈溶解或冻干形式的另外的药物活性成分。
如本文所使用的“治疗”意指整体或部分缓解与病症或疾病相关的症状,或者减慢或停止那些症状的进一步进展或恶化,或者防止或预防具有发展疾病或病症风险的受试者中的疾病或病症。
与式I的化合物有关的术语“有效量”可以意指这样的量,其能够整体或部分缓解与病症或疾病相关的症状,或者减慢或停止那些症状的进一步进展或恶化,或者防止或提供预防患有本文公开的疾病或具有发展所述疾病的风险的受试者中的疾病或病症,所述疾病或病症诸如炎性病症、免疫病症、癌症或代谢病症。
在一个实施方案中,式I的化合物的有效量是诸如例如在体外或体内抑制细胞中的c-KIT激酶的量。在一些实施方案中,与未处理细胞中的c-KIT激酶活性相比,有效量的式I的化合物使细胞中的端锚聚合酶抑制10%、20%、30%、40%、50%、60%、70%、80%、90%或99%。式I的化合物的有效量(例如在药物组合物中)可以为将产生期望效果的水平;例如,对于口服和胃肠外给药两者,在单位剂量中约0.005 mg/kg受试者体重至约10 mg/kg受试者体重。
用途
本发明的化合物适合作为用于哺乳动物、特别是人的药物活性成分,其用于治疗癌症,诸如胃肠道间质瘤。
本发明涵盖式I的化合物和/或其药学上可接受的盐、互变异构体和立体异构体用于制备用于治疗或预防癌症、优选用于治疗胃肠道间质瘤的药物的用途。
优选地,本发明涉及用于治疗疾病的方法,其中所述疾病是癌症,优选胃肠道间质瘤。
特别优选地,本发明涉及方法,其中所述疾病是癌症,其中给药与至少一种其它活性药剂的给药同时、相继或交替。
所公开的式I的化合物可以与其它已知的治疗剂(包括抗癌药)联合给药。如此处所使用的术语“抗癌药”涉及为了治疗癌症目的而向患有癌症的患者给药的任何药剂。
上面定义的抗癌治疗可以作为单一疗法应用,或者除了本文公开的式I的化合物之外还可以涉及常规手术或放射疗法或医学疗法。此类医学疗法,例如化学疗法或靶向疗法可以包括一种或多种,但优选一种,以下抗肿瘤药:
烷基化剂
诸如六甲蜜胺、苯达莫司汀、白消安、卡莫司汀、苯丁酸氮芥、氮芥、环磷酰胺、达卡巴嗪、异环磷酰胺、英丙舒凡、甲苯磺酸盐、洛莫司汀、美法仑、二溴甘露醇、二溴卫矛醇、尼莫司汀、雷莫司汀、替莫唑胺、塞替派、曲奥舒凡、mechloretamine、卡波醌;
阿帕齐醌、福莫司汀、葡膦酰胺、帕磷酰胺、哌泊溴烷、曲磷胺、尿嘧啶氮芥、TH-3024、VAL-0834;
铂化合物
诸如卡铂、顺铂、依他铂、miriplatine水合物、奥沙利铂、洛铂、奈达铂、吡铂、沙铂;
洛铂、奈达铂、吡铂、沙铂;
DNA改变剂
诸如氨柔比星、比生群、地西他滨、米托蒽醌、丙卡巴肼、曲贝替定、氯法拉滨;
安吖啶、溴他利星、匹克生琼、拉罗莫司汀(laromustine)1,3;
拓扑异构酶抑制剂
诸如依托泊苷、伊立替康、雷佐生、索布佐生、替尼泊苷、托泊替康;
氨萘非特、贝洛替康、依利醋铵、伏利拉辛;
微管修饰剂
诸如卡巴他赛、多西他赛、艾立布林、伊沙匹隆、紫杉醇、长春碱、长春新碱、长春瑞滨、长春地辛、长春氟宁;
福他布林、替司他赛;
抗代谢物
诸如天门冬酰胺酶3、阿扎胞苷、左亚叶酸钙、卡培他滨、克拉屈滨、阿糖胞苷、依诺他滨、氟尿苷、氟达拉滨、氟尿嘧啶、吉西他滨、巯嘌呤、甲氨蝶呤、奈拉滨、培美曲塞、普拉曲沙、硫唑嘌呤、硫鸟嘌呤、卡莫氟;
去氧氟尿苷、艾西拉滨、雷替曲塞、沙帕他滨、替加氟2,3、三甲曲沙;
抗癌抗生素
诸如博来霉素、更生霉素、多柔比星、表柔比星、伊达比星、左旋咪唑、米替福新、丝裂霉素C、罗米地新、链佐星、戊柔比星、净司他丁、佐柔比星、柔红霉素(daunurobicin)、普卡霉素;
阿柔比星、培洛霉素、吡柔比星;
激素/拮抗剂
诸如阿巴瑞克、阿比特龙、比卡鲁胺、布舍瑞林、卡普睾酮、氯烯雌醚、地加瑞克、地塞米松、雌二醇、氟可龙氟甲睾酮、氟甲睾酮、氟他胺、氟维司群、戈舍瑞林、组氨瑞林、亮丙瑞林、甲地孕酮、米托坦、那法瑞林、诺龙、尼鲁米特、奥曲肽、泼尼松龙、雷洛昔芬、他莫昔芬、促甲状腺素α、托瑞米芬、曲洛司坦、曲普瑞林、己烯雌酚;
阿考比芬、达那唑、地洛瑞林、环硫雄醇、orteronel、enzalutamide1,3;
芳香酶抑制剂
诸如氨鲁米特、阿那曲唑、依西美坦、法倔唑、来曲唑、睾内酪;
福美坦;
小分子激酶抑制剂
诸如克唑替尼、达沙替尼、厄洛替尼、伊马替尼、拉帕替尼、尼洛替尼、帕唑帕尼、瑞戈非尼、鲁索替尼、索拉非尼、舒尼替尼、凡他尼布、威罗菲尼、波舒替尼、吉非替尼、阿昔替尼;
阿法替尼、alisertib、达拉菲尼、dacomitinib、dinaciclib、度维替尼、恩扎妥林、nintedanib、lenvatinib、linifanib、linsitinib、马赛替尼、米哚妥林、莫替沙尼、奈拉替尼、orantinib、哌立福新、泊那替尼、radotinib、rigosertib、替匹法尼、tivantinib、tivozanib、曲美替尼、pimasertib、丙氨酸布立尼布、西地尼布、apatinib4、苹果酸卡博替尼(cabozantinib S-malate) 1,3、ibrutinib1,3、icotinib4、buparlisib2、cipatinib4、cobimetinib1,3、idelalisib1,3、fedratinib1、XL-6474;
光敏剂
诸如甲氧沙林3;
卟吩姆钠、他拉泊芬、替莫泊芬;
抗体
诸如阿仑珠单抗、贝索单抗、brentuximab vedotin、西妥昔单抗、地舒单抗、伊匹木单抗、奥法木单抗、帕木单抗、利妥昔单抗、托西莫单抗、曲妥珠单抗、贝伐珠单抗、培妥珠单抗2,3;
卡妥索单抗、依洛珠单抗、依帕珠单抗、法利珠单抗、mogamulizumab、奈昔木单抗、尼妥珠单抗、阿托珠单抗、ocaratuzumab、奥戈伏单抗、雷莫芦单抗、利妥木单抗、司妥昔单抗、托珠单抗、扎芦木单抗、扎木单抗、马妥珠单抗、dalotuzumab1,2,3、onartuzumab1,3、雷妥莫单抗1、tabalumab1,3、EMD-5257974、nivolumab1,3;
细胞因子
诸如阿地白介素、干扰素α2、干扰素α2a3、干扰素α2b2,3;
西莫白介素、他索那敏、替西白介素、奥普瑞白介素1,3、重组干扰素β-1a4;
药物缀合物
诸如地尼白介素、替伊莫单抗、碘苄胍I123、泼尼莫司汀、曲妥单抗emtansine、雌莫司汀、吉妥珠单抗、奥加米星、阿柏西普;
贝辛白介素、依度曲肽、伊珠单抗奥加米星、他那莫单抗、莫奥珠单抗、锝(99mTc)阿西莫单抗1,3,
vintafolide1,3;
疫苗
诸如sipuleucel3;vitespen3、emepepimut-S3、oncoVAX4、rindopepimut3、troVax4、MGN-16014、MGN-17034;
其它
阿利维A酸、贝沙罗汀、硼替佐米、依维莫司、伊班膦酸、咪喹莫特、来那度胺、香菇多糖、甲酪氨酸、米法莫肽、帕米磷酸、培门冬酶、喷司他丁、sipuleucel3、西佐喃、他米巴罗汀、坦罗莫司、沙利度胺、维A酸、vismodegib、唑来膦酸、伏林司他;
塞来考昔、西仑吉肽、恩替司他、依他硝唑、ganetespib、伊屈诺昔、iniparib、ixazomib、氯尼达明、尼莫唑、帕比司他、培维A酸、普利肽新、泊马度胺、丙考达唑(procodazol)、地磷莫司、他喹莫德、telotristat、胸腺法新、替拉扎明、托多司他、曲贝德生、乌苯美司、伐司朴达、今又生4、溶血性链球菌制剂4、reolysin4、盐酸瑞他霉素1,3、trebananib2,3、维鲁利秦4、卡非佐米1,3、内皮他丁4、immucothel4、贝林司他3、MGN-17034;
1 Prop. INN (提议的国际非专利名称)
2 Rec. INN (推荐的国际非专利名称)
3 USAN (美国采用的名称)
4无INN。
下列缩写分别是指以下定义:
aq(水性的)、h (小时)、g(克)、L (升)、mg (毫克)、MHz(兆赫)、min.(分钟)、mm (毫米)、mmol (毫摩尔)、mM(毫摩尔的)、m.p.(熔点)、eq (当量)、mL (毫升)、 μL (微升)、ACN(乙腈)、AcOH (乙酸)、CDCl3 (氘化氯仿)、CD3OD (氘化甲醇)、CH3CN (乙腈)、c-hex (环己烷)、DCC (二环己基碳二亚胺)、DCM (二氯甲烷)、DIC (二异丙基碳二亚胺)、DIEA (二异丙基乙胺)、DMF (二甲基甲酰胺)、DMSO (二甲亚砜)、DMSO-d6 (氘化二甲亚砜)、EDC (1-(3-二甲基-氨基-丙基)-3-乙基碳二亚胺)、ESI (电喷射离子化)、EtOAc (乙酸乙酯)、Et2O(乙醚)、EtOH (乙醇)、HATU (二甲基氨基-([1,2,3]三唑并[4,5-b]吡啶-3-基氧基)-亚甲基]-二甲基-铵六氟磷酸盐)、HPLC (高效液相色谱法)、i-PrOH (2-丙醇)、K2CO3 (碳酸钾)、LC(液相色谱法)、MeOH (甲醇)、MgSO4 (硫酸镁)、MS (质谱法)、MTBE (甲基叔丁醚)、NaHCO3(碳酸氢钠)、NaBH4 (硼氢化钠)、NMM (N-甲基吗啉)、NMR (核磁共振)、PyBOP (苯并三唑-1-基-氧基-三-吡咯烷子基-鏻六氟磷酸盐)、RT (室温)、Rt(保留时间)、SPE (固相萃取)、TBTU (2-(1-H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐)、TEA (三乙胺)、TFA(三氟乙酸)、THF (四氢呋喃)、TLC (薄层层析法)、UV (紫外线)。
上文和下文中,所有温度以℃表示。在以下实施例中,“常规后处理(work-up)”意指:如果必要,添加水,如果必要,将pH值调节至2-10之间的值(这取决于终产物的构成),混合物用乙酸乙酯或二氯甲烷萃取,分离各相,有机相经硫酸钠干燥且蒸发,且将残余物通过硅胶上的层析法纯化和/或通过结晶纯化。硅胶上的Rf值;洗脱液:乙酸乙酯/甲醇9:1。
使用氘化溶剂的残留信号作为内部参照,在Bruker DPX-300、DRX-400、AVII-400或500 MHz分光光度仪上记录1H NMR。相对于残留溶剂信号(对于在DMSO-d6中的1H NMR,δ=2.49 ppm)以ppm报道化学位移(δ)。如下报道1H NMR数据:化学位移(多重性、偶合常数和氢的数目)。如下缩写多重性: s(单峰)、d(双峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(宽峰)。
HPLC/MS条件A:
HPLC/MS:Agilent 1200 / 6100
洗脱液A:水 + 0.05%甲酸
洗脱液B:乙腈 + 0.04%甲酸
柱:Chromolith HR RP-18e; 50-4.6 mm
流速:3.3 ml/min
梯度:0% -> 100% B:0.0 -> 2.0 min | 100% B:2.0 -> 2.5 min
UV检测:220 nm
MS检测:65-800 amu正性
HPLC/MS条件B:
HPLC/MS:Agilent 1200 / 6100
洗脱液A:水 + 0.05%甲酸
洗脱液B:乙腈 + 0.04%甲酸
柱:Kinetex XB-C18; 2.6 μm; 50-4.6 mm
流速:2.5 ml/min
梯度:0% -> 100% B:0.0 -> 1.4 min | 100% B:1.4 -> 2.0 min
UV检测:220 nm
MS检测:65-800 amu正性
UPLC/MS条件:
UPLC/MS:Waters Acquity/SQD
洗脱液A:水 + 0.05%甲酸
洗脱液B:乙腈 + 0.04%甲酸
柱:Kinetex XB-C18; 1.7 μm; 50-2.1 mm
流速:0.9 ml/min
梯度:2% -> 100% B:0.0 -> 1.0 min | 100% B:1.0 -> 1.3 min
UV检测:220 nm / 254 nm / MaxPlot / TotalPlot
MS检测:61-800 amu正性。
测定
c-Kit(V654A)测定:
将c-Kit (V654A) (N-末端GST-标记的重组人c-Kit,含有V654A突变的氨基酸544-末端)与8 mM MOPS pH 7.0、0.2 mM EDTA、250 µM GGMEDIYEFMGGKKK、10 mM乙酸镁和[γ-33P-ATP](比活性近似500 cpm/pmol,浓度200μM)一起孵育。通过添加MgATP混合物来引发反应。在室温下孵育40分钟后,通过添加3%磷酸溶液来终止反应。然后将10μL反应物点至P30滤垫上,并在75 mM磷酸中洗涤三次5分钟,并在甲醇中洗涤一次,然后干燥和闪烁计数。
PDGFRα(V561D)测定:
将PDGFRα(V561D) (N-末端6His-标记的重组人PDGFRα,含有V561D突变的氨基酸550-末端)与8 mM MOPS pH 7.0、0.2 mM EDTA、250 µM GGMEDIYEFMGGKKK、10 mM乙酸镁和[γ-33P-ATP](比活性近似500 cpm/pmol,浓度200μM)一起孵育。通过添加MgATP混合物来引发反应。在室温下孵育40分钟后,通过添加3%磷酸溶液来终止反应。然后将10μL反应物点至P30滤垫上,并在75 mM磷酸中洗涤三次5分钟,并在甲醇中洗涤一次,然后干燥和闪烁计数。
药理学数据
表 1 式I的化合物的c-KIT (V654A)和PDGFRα (V561D)的抑制(IC50)
解释:1.4E-06意指1.4 x 10-6
表1中所示的化合物是根据本发明的特别优选的化合物。
中间体的合成
溴喹诺酮类化合物和溴萘啶酮类化合物
3-溴-6-氟-1H-喹啉-2-酮的合成
将2-氨基-5-氟-苯甲醛 (7.42 g, 53.3 mmol)于丙二酸二甲酯(45 ml)中的溶液加热至140℃并在该温度下搅拌16小时。使反应混合物达到室温。将所得沉淀滤出,用叔丁基甲基醚洗涤并在真空下干燥,以得到作为浅赭色固体的6-氟-2-氧代-1,2-二氢-喹啉-3-甲酸甲酯;HPLC/MS 1.17 min (B), [M+H]+ 222。
1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 8.49 (s, 1H), 7.70 (dd, J =9.0, 2.9 Hz, 1H), 7.52 (td, J = 8.9, 2.9 Hz, 1H), 7.35 (dd, J = 9.1, 4.7 Hz,1H), 3.81 (s, 3H)。
向6-氟-2-氧代-1,2-二氢-喹啉-3-甲酸甲酯(6.92 g, 31,3 mmol)于THF (30ml)和水(38 ml)的混合物中的浆液中添加氢氧化锂(6.59 g, 275 mmol),并将混合物在65℃下搅拌2小时。在冷却至室温后,添加1 N盐酸水溶液,直至达到1的pH值。将所得沉淀滤出,用水洗涤并在真空下干燥,以得到作为浅黄色固体的6-氟-2-氧代-1,2-二氢-喹啉-3-甲酸;HPLC/MS 1.18 min (B), [M+H]+ 208。
将6-氟-2-氧代-1,2-二氢-喹啉-3-甲酸(6.70 g, 32.3 mmol)于吡啶(108 ml)中的悬浮液冷却至0℃。在搅拌和连续外部冷却下,逐滴添加溴(6.63 ml, 129 mmol)。将反应混合物加热至65℃并在该温度下搅拌1小时。在冷却至室温后,将反应混合物倒入水(160ml)中。添加37%盐酸水溶液,直至达到4的pH值。将所得沉淀滤出并用水洗涤。将滤液用二氯甲烷萃取三次;将有机相合并,经硫酸钠干燥并蒸发。将残余物与沉淀合并,并在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,以得到作为浅黄色固体的3-溴-6-氟-1H-喹啉-2-酮;HPLC/MS 1.26 min (B), [M+H]+ 242,244。
1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.49 (s, 1H), 7.54 (dd, J =9.1, 2.8 Hz, 1H), 7.46 (td, J = 8.8, 2.8 Hz, 1H), 7.36 (dd, J = 9.0, 4.8 Hz,1H)。
类似地制备以下化合物
3-溴-6-氯-1H-[1,8]萘啶-2-酮,浅棕色固体; HPLC/MS 1.24 min (B), [M+H]+ 261。
3-溴-6-甲氧基-1H-[1,8]萘啶-2-酮,棕色固体; HPLC/MS 1.12 min (B), [M+H]+ 255,257。
1H NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 8.49 (s, 1H), 8.36 (d, J =3.0 Hz, 1H), 7.75 (d, J = 3.0 Hz, 1H), 3.86 (s, 3H)。
3-溴-1H-[1,8]萘啶-2-酮,棕色固体; HPLC/MS 1.09 min (B), [M+H]+ 225,227。
1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.56 (m, 2H), 8.13 (d,1H), 7.30 (dd, 1H)。
3-溴-1H-[1,7]萘啶-2-酮,橙色-棕色固体; HPLC/MS 1.00 min (B), [M+H]+225,227。
3-溴-7-甲基-1H-[1,8]萘啶-2-酮,浅黄色固体; HPLC/MS 1.16 min (B), [M+H]+ 239,241。
3-溴-6-氟-1H-[1,8]萘啶-2-酮,米黄色固体; HPLC/MS 1.15 min (B), [M+H]+243,245。
1H NMR (500 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.62 (d, J = 2.8 Hz, 1H),8.52 (s, 1H), 8.08 (dd, J = 8.5, 2.9 Hz, 1H)。
乙炔基-喹诺酮类化合物和乙炔基-萘啶酮类化合物
3-乙炔基-1H-喹啉-2-酮的合成
向3-溴-1H-喹啉-2-酮 (2.24 g, 10.0 mmol)于二氧杂环己烷 (40 ml)中的悬浮液中添加三乙胺(3.67 ml, 26.5 mmol)和碘化亚铜(I)(1.90 g, 10.0 mmol)。将反应混合物用氮气吹扫并添加双(三苯基膦)氯化钯(II)(286 mg, 0.40 mmol)和三甲基甲硅烷基-乙炔(2.37 ml, 17.1 mmol)。将反应混合物用氮气冲洗并在80℃下在封闭的反应小瓶中搅拌16小时。使反应混合物达到室温并过滤通过硅藻土塞。将残余物用二氯甲烷洗涤并蒸发滤液。将残余物在硅胶柱上用环己烷/乙酸乙酯作为洗脱液进行色谱分离,以得到作为浅棕色固体的3-三甲基甲硅烷基乙炔基-1H-喹啉-2-酮;HPLC/MS 1.52 min (B), [M+H]+ 242。
向3-三甲基甲硅烷基乙炔基-1H-喹啉-2-酮(2.16 g, 8.95 mmol)于甲醇(18 ml)中的溶液中添加氧化铝上的氟化钾(1.04 g, ~ 5.7 mmol氟化物)并将反应混合物在室温下搅拌30分钟。将反应混合物倒入冰水中。将固体滤出,用水洗涤并在真空下干燥。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,以得到作为浅棕色固体的3-乙炔基-1H-喹啉-2-酮;HPLC/MS 1.18 min (B), [M+H]+ 170。
1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.23 (s, 1H), 7.67 (dd, J= 7.9, 1.4 Hz, 1H), 7.53 (ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 7.34 – 7.27 (m,1H), 7.20 (ddd, J = 8.1, 7.2, 1.1 Hz, 1H), 4.34 (s, 1H)。
类似地制备以下化合物:
6-氯-3-乙炔基-1H-[1,8]萘啶-2-酮,浅米黄色固体; HPLC/MS 1.20 min (B), [M+H]+ 205。
3-乙炔基-6-甲氧基-1H-[1,8]萘啶-2-酮,米黄色固体; HPLC/MS 1.11 min (B),[M+H]+ 201。
1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.30 (d, J = 3.0 Hz, 1H),8.18 (s, 1H), 7.72 (d, J = 3.0 Hz, 1H), 4.41 (s, 1H), 3.84 (s, 3H)。
3-乙炔基-6-氟-1H-喹啉-2-酮,米黄色固体; HPLC/MS 1.27 min (A), [M+H]+188。
3-乙炔基-1H-[1,7]萘啶-2-酮,米黄色粉末; HPLC/MS 0.97 min (B), [M+H]+171;
1H NMR (400 MHz, DMSO-d6) δ 12.28 (bs, 1H) 8.60 (s, 1H), 8.22 (d, J = 5.2Hz, 1H), 8.14 (s, 1H), 7.51 (d, J = 5.2 Hz, 1H), 4.41 (s, 1H)。
3-乙炔基-7-甲基-1H-[1,8]萘啶-2-酮,米黄色固体; HPLC/MS 1.13 min (B),[M+H]+ 185;
3-乙炔基-6-氟-1H-[1,8]萘啶-2-酮,橙色-米黄色固体; HPLC/MS 1.11 min (B), [M+H]+ 189;
1H NMR (500 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.47 (d, J = 2.8 Hz, 1H), 8.10(s, 1H), 7.96 (dd, J = 8.5, 3.0 Hz, 1H), 4.38 (s, 1H)。
芳香族叠氮化物
4-(4-叠氮基-苯基)-3-氧代-哌嗪-1-甲酸叔丁酯的合成
向4-(4-氨基-苯基)-3-氧代-哌嗪-1-甲酸叔丁酯(4.37 g, 15.0 mmol)于乙醇(47ml)和水(47 ml)的混合物中的搅拌溶液中添加盐酸水溶液(37%, 9.15 ml)。将溶液冷却至0℃,并缓慢添加亚硝酸钠(1.24 g, 18.0 mmol)于水(10 ml)中的溶液。将反应混合物在室温下搅拌10分钟。然后分部分添加叠氮化钠(1.46 g, 22.5 mmol),并将反应混合物在室温下搅拌2小时。将反应混合物倒入水中,将固体滤出,用水洗涤并在真空下干燥,以得到作为米黄色固体的4-(4-叠氮基-苯基)-3-氧代-哌嗪-1-甲酸叔丁酯;HPLC/MS 1.60 min (A),[M+H]+ 318。
1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.8Hz, 2H), 4.06 (s, 2H), 3.76 – 3.62 (m, 4H), 1.44 (s, 9H)。
类似地制备以下化合物
(4-叠氮基-苄基)-二甲基-胺; 1H NMR (400 MHz, CDCl3) δ 7.46 (d, 2H), 6.99(d, 2H), 3.38 (s, 2H), 2.25 (s, 6H)。
(4-叠氮基-苯基)-甲醇; 1H NMR (400 MHz, DMSO-d6) δ 7.36 (d, 2H), 7.07(d, 2H), 5.25 t, 1H), 4.49 (d, 2H)。
1-[2-(4-叠氮基-苯氧基)-乙基]-吡咯烷,棕色油状物; HPLC/MS 1.07 min (B),[M+H]+ 233。
4-[2-(4-叠氮基-苯氧基)-乙基]-吗啉,棕色油状物; HPLC/MS 1.05 min (B),[M+H]+ 249。
1H NMR (400 MHz, DMSO-d6) δ 7.08 – 6.96 (m, 4H), 4.08 (t, J = 5.8 Hz,2H), 3.56-3.60 (m, 4H), 2.68 (t, J = 5.8 Hz, 2H), 2.44-2.49 (m, 2H)。
4-(5-叠氮基-嘧啶-2-基)-哌嗪-1-甲酸叔丁酯,棕色固体; HPLC/MS 1.83 min(A), [M-tbu]+ 250。
1H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 2H), 3.72 – 3.65 (m, 4H), 3.46 –3.36 (m, 4H), 1.42 (s, 9H)。
4-[2-(4-叠氮基-苯氧基)-乙基]-哌嗪-1-甲酸叔丁酯,米黄色粉末; HPLC/MS1.30 min (A), [M+H]+ 348。
4-(4-叠氮基-苯基)-哌嗪-1-甲酸叔丁酯,棕色固体; HPLC/MS 1.94 min (A),[M+H]+ 304。
4-(4-叠氮基-苯基)-[1,4]二氮杂环庚烷-1-甲酸叔丁酯,棕色油状物; HPLC/MS1.97 min (A), [M+H]+ 318。
4-(4-叠氮基-苯基)-[1,4]二氮杂环庚烷-1-甲酸叔丁酯,棕色油状物; HPLC/MS1.97 min (A), [M+H]+ 318。
(4-叠氮基-3-甲基-苯基)-吗啉-4-基-甲酮,黄色树脂; HPLC/MS 1.42 min (A),[M+H]+ 247。
5-叠氮基-1,2,3-三甲氧基-苯,米黄色固体; HPLC/MS 1.56 min (A), [M+H]+210。
1H NMR (400 MHz, DMSO-d6) δ 6.42 (s, 2H), 3.80 (s, 6H), 3.64 (s, 3H)。
(4-叠氮基-2-氟-苯基)-吗啉-4-基-甲酮,浅棕色油状物; HPLC/MS 1.31 min(A), [M+H]+ 251。
4-叠氮基-2-氟-N-甲基-苯甲酰胺,浅棕色油状物; HPLC/MS 1.23 min (A), [M+H]+ 195。
4-[2-(3-叠氮基-苯氧基)-乙基]-吗啉,棕色油状物; HPLC/MS 1.03 min (A),[M+H]+ 249。
3-(4-叠氮基-苯基)-噁唑烷-2-酮,淡棕色粉末; HPLC/MS 1.44 min (A), [M+H]+ 205. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 9.0 Hz, 2H), 7.15 (d, J = 9.0Hz, 2H), 4.59 – 4.33 (m, 2H), 4.10 – 4.00 (m, 2H)。
2-(4-叠氮基-苯基)-异噻唑烷 1,1-二氧化物,米黄色粉末; HPLC/MS 1.47 min(A), [M+H]+ 239。
4-(4-叠氮基-苯磺酰基)-哌嗪-1-甲酸叔丁酯,浅黄色固体; UPLC/MS 0.90 min,[M+H]+ 268。
4-(4-叠氮基-苯磺酰基)-哌嗪-1-甲酸叔丁酯,米黄色固体; HPLC/MS 1.93 min(A), [M+H]+ 275。
4-[2-(4-叠氮基-苯基)-乙酰基]-哌嗪-1-甲酸叔丁酯,浅黄色固体; UPLC/MS1.13 min, [M-tBu]+ 290. 1H NMR (400 MHz, DMSO-d6) δ 7.31 – 7.25 (m, 2H), 7.15– 7.04 (m, 2H), 3.72 (s, 2H), 3.50 – 3.42 (m, 4H), 3.30 – 3.23 (m, 4H), 1.41(s, 9H)。
[2-(4-叠氮基-苯基)-乙基]-二甲基-胺,红色-棕色油状物; UPLC/MS 0.77 min,[M+H]+ 191. 1H NMR (500 MHz, DMSO-d6) δ 7.27 (d, J = 8.4 Hz, 2H), 7.07 – 6.99(m, 2H), 2.75 – 2.66 (m, 2H), 2.47 – 2.38 (m, 2H), 2.17 (s, 6H)。
1-[2-(4-叠氮基-苯基)-乙基]-吡咯烷,红色-棕色油状物; UPLC/MS 0.78 min,[M+H]+ 217. 1H NMR (500 MHz, DMSO-d6) δ 7.30 – 7.26 (m, 1H), 7.06 – 7.01 (m,1H), 2.73 (t, J = 7.6 Hz, 1H), 2.60 (t, J = 7.6 Hz, 1H), 2.49 – 2.43 (m, 3H),1.71 – 1.63 (m, 4H)。
[2-(4-叠氮基-苯氧基)-乙基]-二乙基-胺,棕色液体; HPLC/MS 1.08 min (A),[M+H]+ 235。
4-(4-叠氮基-苯基)-吗啉-3-酮的合成
将4-(4-氨基-苯基)-吗啉-3-酮(3.00 g, 15.6 mmol)于乙腈(35 ml)中的悬浮液冷却至0℃。然后逐滴添加亚硝酸丁酯(2.43 g, 23.6 mmol)。将反应混合物在0℃下搅拌15分钟。然后逐滴添加三甲基甲硅烷基叠氮化物。将反应混合物在室温下搅拌20小时。将反应混合物在减压下浓缩并将残余物在硅胶柱上用环己烷/乙酸乙酯作为洗脱液进行色谱分离,以得到作为米黄色固体的4-(4-叠氮基-苯基)-吗啉-3-酮;HPLC/MS 1.21 min (B), [M+H]+ 219。
1H NMR (300 MHz, DMSO-d6) δ 7.45 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.8Hz, 2H), 4.20 (s, 2H), 4.04 – 3.92 (m, 2H), 3.81 – 3.66 (m, 2H)。
类似地制备以下化合物
4-(4-叠氮基-苯氧基甲基)-哌啶-1-甲酸叔丁酯,米黄色固体; HPLC/MS 1.85 min(B), [M-tbu]+ 277。
4-(4-叠氮基-2-氟-苯基)-吗啉-3-酮,黄色粉末; HPLC/MS 1.27 min (A), [M+H]+ 237。
1H NMR (400 MHz, DMSO-d6) δ 7.49 (t, J = 8.4 Hz, 1H), 7.17 (dd, J =11.0, 2.5 Hz, 1H), 7.05 (ddd, J = 8.6, 2.5, 1.0 Hz, 1H), 4.22 (s, 2H), 4.03 –3.82 (m, 2H), 3.73 – 3.58 (m, 2H)。
4-(5-叠氮基-吡啶-2-基)-吗啉-3-酮,黄色固体; HPLC/MS 1.15 min (A), [M+H]+ 220。
1H NMR (400 MHz, DMSO-d6) δ 8.27 (dd, J = 2.9, 0.7 Hz, 1H), 8.05 (dd,J = 8.9, 0.7 Hz, 1H), 7.69 (dd, J = 8.9, 2.9 Hz, 1H), 4.27 (s, 2H), 4.05 –3.90 (m, 4H)。
2-(4-叠氮基-苯基)-丙-2-醇的合成
向2-(4-溴-苯基)-丙-2-醇(1.00 g, 4.65 mmol)、碘化亚铜(I)(177 mg, 0.93 mmol)和(2R)-2-[(2R)-3,4-二羟基-5-氧代-2H-呋喃-2-基]-2-羟基-乙醇钠水合物(100 mg,0.46 mmol)于DMF (4 ml)和水(5 ml)的混合物中的悬浮液中添加叠氮化钠(605 mg, 9.3mmol)和N,N'-二甲基-乙烷-1,2-二胺(123 mg, 1.39 mmol)。将反应混合物在室温下搅拌19小时。将反应混合物倒入40 ml饱和氯化钠水溶液中。将混合物用乙酸乙酯萃取。将有机相经硫酸钠干燥并蒸发。将残余物在硅胶柱上用环己烷/乙酸乙酯作为洗脱液进行色谱分离,以得到作为浅棕色油状物的2-(4-叠氮基-苯基)-丙-2-醇;HPLC/MS 1.47 min (B),[M-N2-OH]+ 132。
1H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4Hz, 2H), 5.01 (s, 1H), 1.41 (s, 6H)。
类似地制备以下化合物
5-叠氮基-1H-吲哚,暗棕色油状物; HPLC/MS 1.46 min (B), [M+H]+ 159。
1H NMR (300 MHz, DMSO-d6) δ 11.19 (s, 1H), 7.43 (dt, J = 8.6, 0.8 Hz,1H), 7.40 (t, J = 2.8 Hz, 1H), 7.29 (dt, J = 2.2, 0.7 Hz, 1H), 6.84 (dd, J =8.6, 2.2 Hz, 1H), 6.42 (ddd, J = 3.0, 2.0, 0.9 Hz, 1H)。
(5-叠氮基-吲哚-1-基)-乙酸甲酯,黑色胶状物; HPLC/MS 1.72 min (A), [M+H]+ 231。
1H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 3.2Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 6.91 (d, J = 2.2 Hz, 1H), 6.89 (d, J = 2.2Hz, 1H), 6.47 (dd, J = 3.2, 0.8 Hz, 2H), 5.16 (s, 1H), 3.69 (s, 3H)。
(4-叠氮基-苯基)-吗啉-4-基-甲酮的合成
向4-叠氮基苯甲酸(2.50 g, 15.3 mmol)、吗啉(1.35 ml, 15.5 mmol)和[二甲基氨基(三唑并[4,5-b]吡啶-3-基氧基)亚甲基]-二甲基-六氟磷酸铵(HATU; 5.85 g, 15.4mmol)于DMF (30 ml)中的溶液中添加乙基-二异丙基-胺(7.90 ml, 46.5 mmol)并将反应混合物在室温下搅拌16小时。向反应混合物中添加乙酸乙酯、饱和Na2CO3水溶液和水。将有机相分离,用水、2N HCl水溶液和饱和氯化钠溶液洗涤。将有机相经硫酸钠干燥并蒸发。将残余物在硅胶柱上用环己烷/乙酸乙酯作为洗脱液进行色谱分离,以得到作为无色油状物的(4-叠氮基-苯基)-吗啉-4-基-甲酮,其在静置后结晶;HPLC/MS 1.27 min (A), [M+H]+233。
1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5Hz, 2H), 3.38-3-66 (m, 8H)。
类似地制备以下化合物:
4-叠氮基-N,N-二甲基苯甲酰胺,棕色油状物; HPLC/MS 2.24 min (A), [M+H]+ 191。
4-[(4-叠氮基-苯甲酰基)-甲基-氨基]-哌啶-1-甲酸叔丁酯,黄色油状物; HPLC/MS 1.42 min (B), [M-tbu]+ 304。
1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, J = 8.5 Hz, 2H), 7.24 – 7.08 (m,1H), 4.41 (m, 1H), 4.02 (m, 4H), 2.79 (s, 3H), 1.73 – 1.51 (m, 4H), 1.41 (s,9H)。
4-叠氮基-N-(2-羟基-乙基)-苯甲酰胺,白色晶体; HPLC/MS 1.10 min (B), [M+H]+ 207。
4-叠氮基-N-(2-甲氧基-乙基)-苯甲酰胺。
[1-(4-叠氮基-苯甲酰基)-哌啶-4-基]-氨基甲酸 叔丁酯,浅黄色玻璃状物;HPLC/MS 1.45 min (B), [M+H]+ 346。
1H NMR (400 MHz, DMSO-d6) δ 7.40 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 8.5Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 4.10-4.40 (m, 1H), 3.45-3.60 (m, 2H),2.85-3.15 (m, 2H), 1.65-1.85 (m, 2H), 1.38 (s, 9H), 1.20-1.40 (m, 2H)。
4-(4-叠氮基-苯甲酰基)-哌嗪-1-甲酸叔丁酯,浅黄色固体; HPLC/MS 1.49 min(B), [M-tbu]+ 276。
1H NMR (300 MHz, DMSO-d6) δ 7.47 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5Hz, 2H), 3.30-3.62 (m, 8H), 1.42 (s, 9H)。
4-叠氮基-N-(2-吗啉-4-基-乙基)-苯甲酰胺,棕色玻璃状物; HPLC/MS 0.98 min(B), [M+H]+ 276。
4-(4-叠氮基-苯甲酰基氨基)-哌啶-1-甲酸叔丁酯,浅黄色固体; HPLC/MS 1.49min (B), [M-tbu]+ 290。
1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 8.6Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 3.90-4.03 (m, 3H), 2.77-2.94 (m, 2H),1.75-1.82 (m, 2H), 1.42 (s, 9H), 1.36 – 1.48 (m, 2H)。
4-叠氮基-N-(1-甲基-哌啶-4-基甲基)-苯甲酰胺,浅黄色油状物; HPLC/MS 1.00min (B), [M+H]+ 274。
(4-叠氮基-2-甲基-苯基)-吗啉-4-基-甲酮,棕色树脂; HPLC/MS 1.35 min (A),[M+H]+ 247。
(4-叠氮基-苯基)-[4-(3-甲氧基-丙基)-哌嗪-1-基]-甲酮,棕色油状物; HPLC/MS 1.00 min (A), [M+H]+ 304。
4-(3-叠氮基-苯甲酰基)-哌嗪-1-甲酸叔丁酯,米黄色固体; HPLC/MS 1.69 min(A), [M+H]+ 232。
4-(4-叠氮基-苯甲酰基)-1-甲基-哌嗪-2-酮,浅黄色胶状物; HPLC/MS 1.18 min(A), [M+H]+ 269。
1H NMR (400 MHz, DMSO-d6) δ 7.55 – 7.47 (m, 2H), 7.24 – 7.17 (m, 2H),4.06 (s, 1H), 3.87 – 3.54 (m, 2H), 3.36 (t, J = 5.5 Hz, 1H), 2.86 (s, 3H)。
(4-叠氮基-苯基)-((R)-3-羟基-吡咯烷-1-基)-甲酮,淡棕色油状物; HPLC/MS1.16 min (A), [M+H]+ 233。
(4-叠氮基-苯基)-((S)-3-羟基-吡咯烷-1-基)-甲酮,淡棕色油状物; HPLC/MS1.16 min (A), [M+H]+ 233。
(4-叠氮基-苯基)-[1,3’]联吡咯烷基-1’-甲酮,棕色胶状物; HPLC/MS 0.94 min(A), [M+H]+ 286。
1-(4-叠氮基-苯甲酰基)-4-甲基-[1,4]二氮杂环庚烷-5-酮,黄色树脂; UPLC/MS0.51 min, [M+H]+ 274。
乙酸1-(4-叠氮基-苯甲酰基)-哌啶-4-基酯,黄色树脂; HPLC/MS 1.48 min (A),[M+H]+ 289。
1H NMR (400 MHz, DMSO-d6) δ 7.38 (d, J = 8.5 Hz, 2H), 7.16 – 6.99 (m,2H), 4.87 (tt, J = 7.9, 3.8 Hz, 1H), 4.06 – 3.11 (m, 4H), 1.93 (s, 3H), 1.80(bs, 2H), 1.53 (bs, 2H)。
4-[2-(5-叠氮基-吲哚-1-基)-乙酰基]-哌嗪-1-甲酸叔丁酯的合成
4-[2-(5-叠氮基-吲哚-1-基)-乙酰基]-哌嗪-1-甲酸叔丁酯,浅米黄色固体; UPLC/MS0.84 min, [M+H]+ 329。
4-[2-(4-叠氮基-苯氧基)-乙酰基]-哌嗪-1-甲酸叔丁酯的合成
4-[2-(4-叠氮基-苯氧基)-乙酰基]-哌嗪-1-甲酸叔丁酯,黄色固体; UPLC/MS 0.84min, [M+H]+ 306。
4-[2-(5-叠氮基-吲唑-1-基)-乙酰基]-哌嗪-1-甲酸叔丁酯的合成
4-[2-(5-叠氮基-吲唑-1-基)-乙酰基]-哌嗪-1-甲酸叔丁酯,紫色固体, UPLC/MS1.04 min, [M+H]+ 386。
三唑基-乙酸类化合物
4-[4-(4-羧基甲基-[1,2,3]三唑-1-基)-苯甲酰基]-哌嗪-1-甲酸叔丁酯的合成
向硫酸铜(II)五水合物(86 mg, 0.54 mmol)和(2R)-2-[(2R)-3,4-二羟基-5-氧代-2H-呋喃-2-基]-2-羟基-乙醇钠水合物(116 mg, 0.54 mmol)于叔丁醇(10 ml)和水(10ml)的混合物中的悬浮液中添加3-丁炔酸(451 mg, 5.37 mmol)和4-(4-叠氮基-苯甲酰基)-哌嗪-1-甲酸叔丁酯(1.78 g, 5.37 mmol)。将反应混合物在80℃下搅拌19小时。使反应混合物达到室温,并倒入水中。将所得沉淀滤出,用水洗涤并干燥。将残余物用叔丁基甲基醚研磨,以得到作为米黄色粉末的 4-[4-(4-羧基甲基-[1,2,3]三唑-1-基)-苯甲酰基]-哌嗪-1-甲酸叔丁酯。可以通过用乙酸乙酯萃取滤液来获得第二批产物。HPLC/MS 1.36 min(A), [M+H]+ 416。
1H NMR (400 MHz, DMSO-d6, d-TFA) δ 8.59 (s, 1H), 7.99 (d, J = 8.5 Hz,2H), 7.64 (d, J = 8.5 Hz, 2H), 3.84 (s, 2H), 3.35-3.75 (m, 8H), 1.45 (s, 9H)。
类似地制备以下化合物:
[1-(4-氟-苯基)-1H-[1,2,3]三唑-4-基]-乙酸,浅棕色固体; HPLC/MS 1.18 min(B), [M+H]+ 222。
1H NMR (400 MHz, DMSO-d6, d-TFA) δ 8.48 (s, 1H), 7.86 (dd, J = 9.0,4.6 Hz, 2H), 7.27 (t, J = 8.7 Hz, 2H), 3.73 (s, 2H)。
{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,米黄色固体; HPLC/MS 1.01 min (A), [M+H]+ 317。
1H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 8.73 (s, 1H), 8.35 – 7.83(m, 2H), 7.86 – 7.52 (m, 2H), 3.80 (s, 2H), 3.48 (d, J = 124.8 Hz, 9H)。
4-[4-(4-羧基甲基-[1,2,3]三唑-1-基)-苯基]-哌嗪-1-甲酸叔丁酯,灰色固体;HPLC/MS 1.51 min (A), [M+H]+ 388。
1H NMR (400 MHz, DMSO-d6, d-TFA) δ 8.56 (s, 1H), 7.85 (d, J = 8.7 Hz,2H), 7.34 (d, J = 8.8 Hz, 2H), 3.81 (s, 2H), 3.58-3.64 (m, 4H), 3.33-3-39 (m,4H), 1.46 (s, 9H)。
{1-[4-(3-氧代-吗啉-4-基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,米黄色固体;HPLC/MS 1.06 min (A), [M+H]+ 303。
1H NMR (400 MHz, DMSO-d 6, TFA-d1) δ 8.58 (s, 1H), 7.90 (d, J = 8.8 Hz,2H), 7.60 (d, J = 8.8 Hz, 2H), 4.21 (s, 2H), 3.99 – 3.95 (m, 2H), 3.82 – 3.71(m, 4H)。
(1-{4-[4-(3-甲氧基-丙基)-哌嗪-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-乙酸,米黄色固体; HPLC/MS 0.86 min (A), [M+H]+ 388。
4-[4-(4-羧基甲基-[1,2,3]三唑-1-基)-苯基]-[1,4]二氮杂环庚烷-1-甲酸叔丁酯,紫罗兰色固体; HPLC/MS 1.52 min (A), [M+H]+ 402。
4-(3-叠氮基-苯甲酰基)-哌嗪-1-甲酸叔丁酯,米黄色固体; HPLC/MS 1.38 min(A), [M+H]+ 416。
{1-[4-(4-甲基-3-氧代-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,浅黄色粉末; UPLC/MS 0.40 min, [M+H]+ 344。
{1-[3-(2-吗啉-4-基-乙氧基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,米黄色固体; HPLC/MS 0.88 min (A), [M+H]+ 333。
[1-(1-甲氧基羰基甲基-1H-吲哚-6-基)-1H-[1,2,3]三唑-4-基]-乙酸,浅棕色固体; HPLC/MS 1.25 min (A), [M+H]+ 315. 1H NMR (400 MHz, DMSO-d6) δ 12.61 (bs,1H), 8.56 (s, 1H), 8.03 (t, J = 1.3 Hz, 1H), 7.63 -7.61 (m, 2H), 7.51 (d, J =3.2 Hz, 1H), 6.62 (d, J = 3.2 Hz, 1H), 5.24 (s, 2H), 3.78 (s, 2H), 3.71 (s,3H)。
{1-[4-((R)-3-羟基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,暗棕色油状物; HPLC/MS 0.95 min (A), [M+H]+ 317。
{1-[4-((S)-3-羟基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,暗棕色油状物; HPLC/MS 0.95 min (A), [M+H]+ 317。
{1-[4-(2-氧代-噁唑烷-3-基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,棕色粉末;HPLC/MS 1.08 min (A), [M+H]+ 289。1H NMR (400 MHz, DMSO-d 6, TFA-d1) δ 8.63 (s,1H), 8.19 – 7.87 (m, 2H), 7.87 – 7.70 (m, 2H), 4.50 (m, 2H), 4.16 (m, 2H),3.80 (s, 2H)。
{1-[4-(1,1-二氧代-异噻唑烷-2-基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,棕色粉末; HPLC/MS 1.11 min (A), [M+H]+ 323。
{1-[4-(1,1-二氧代-异噻唑烷-2-基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,棕色粉末; HPLC/MS 1.11 min (A), [M+H]+ 323。
{1-[4-([1,3']联吡咯烷基-1'-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,棕色固体; HPLC/MS 0.84 min (A), [M+H]+ 370。
{1-[4-(4-甲基-5-氧代-[1,4]二氮杂环庚烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,棕色固体; UPLC/MS 0.40 min, [M+H]+ 358。
4-[4-(4-羧基甲基-[1,2,3]三唑-1-基)-苯甲酰基]-哌啶-1-甲酸叔丁酯,米黄色固体; HPLC/MS 1.57 min (A), [M+H]+ 415。
{1-[4-(4-乙酰氧基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,米黄色固体; HPLC/MS 1.17 min (A), [M+H]+ 373。
{1-[4-(3-乙酰氧基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,浅棕色泡沫; HPLC/MS 1.18 min (A), [M+H]+ 373。
4-{2-[4-(4-羧基甲基-[1,2,3]三唑-1-基)-苯氧基]-乙基}-哌嗪-1-甲酸叔丁酯,棕色固体; HPLC/MS 1.10 min (A), [M+H]+ 432。
4-{3-[4-(4-羧基甲基-[1,2,3]三唑-1-基)-苯氧基]-丙基}-哌嗪-1-甲酸叔丁酯,棕色粉末; HPLC/MS 1.12 min (A), [M+H]+ 446。
{1-[4-(3-甲氧基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,棕色泡沫; HPLC/MS 1.13 min (A), [M+H]+ 345。
{1-[3-([1,3']联吡咯烷基-1'-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,浅棕色固体; HPLC/MS 0.84 min (A), [M+H]+ 370。
4-{2-[4-(4-羧基甲基-[1,2,3]三唑-1-基)-苯氧基]-乙基}-哌啶-1-甲酸叔丁酯,棕色油状物,其缓慢结晶; HPLC/MS 1.73 min (A), [M+H]+ 431。
{1-[4-((R)-3-甲氧基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,绿色树脂; UPLC/MS 0.73 min, [M+H]+ 331。
{1-[4-((S)-3-甲氧基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,绿色树脂; UPLC/MS 0.73 min, [M+H]+ 331。
4-{2-[4-(4-羧基甲基-[1,2,3]三唑-1-基)-苯基]-乙酰基}-哌嗪-1-甲酸叔丁酯,米黄色固体; UPLC/MS 0.92 min [M+H]+ 430。
{1-[4-(4-叔丁氧基羰基氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,米黄色固体; UPLC/MS 0.90 min [M+H]+ 430。
1H NMR (500 MHz, DMSO-d6) δ 12.59 (s, 1H), 8.72 (s, 1H), 8.12 – 7.73(m, 2H), 7.58 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 7.7 Hz, 1H), 4.33 (bs, 1H),3.80 (s, 2H), 3.55 (bs, 2H), 3.14 (bs, 1H), 2.99 (bs, 1H), 1.77 (m, 2H), 1.40(m, 11H)。
4-{2-[5-(4-羧基甲基-[1,2,3]三唑-1-基)-吲哚-1-基]-乙酰基}-哌嗪-1-甲酸叔丁酯,米黄色固体; UPLC/MS 0.92 min, [M+H]+ 469。
4-{2-[4-(4-羧基甲基-[1,2,3]三唑-1-基)-苯氧基]-乙酰基}-哌嗪-1-甲酸叔丁酯,灰白色固体; UPLC/MS 0.92 min, [M+H]+ 446。
{1-[4-(2-二甲基氨基-乙基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,暗棕色残余物; UPLC/MS 0.63 min, [M+H]+ 275。
{1-[4-(2-吡咯烷-1-基-乙基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,暗棕色固体; UPLC/MS 0.65 min, [M+H]+ 301。
4-[4-(4-羧基甲基-[1,2,3]三唑-1-基)-苯基]-3-氧代-哌嗪-1-甲酸叔丁酯,米黄色固体; HPLC/MS 1.34 min (A), [M+H]+ 402。
4-{2-[5-(4-羧基甲基-[1,2,3]三唑-1-基)-吲唑-1-基]-乙酰基}-哌嗪-1-甲酸叔丁酯,灰色粉末; UPLC/MS 0.88 min, [M+H]+ 470。
{1-[4-(2-二乙基氨基-乙氧基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸, 棕色残余物; HPLC/MS 0.91 min (A), [M+H]+ 391。
{1-[4-(2-吡咯烷-1-基-乙氧基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸,棕色固体泡沫; HPLC/MS 0.89 min (A), [M+H]+ 317。
2-氨基苯甲醛类化合物
6-氨基-2,3-二氟-苯甲醛的合成
将2,3-二氟-6-氨基苯甲酸(1.00 g, 5.78 mmol)于THF (30 ml)中的悬浮液在氮气下冷却至0℃。在30分钟内逐滴添加氢化铝锂(THF中的1.0 M溶液, 8.7 ml, 8.7 mmol)。将反应混合物在0℃下搅拌1小时并在室温下搅拌18小时。将反应混合物用水淬灭并经硅藻土过滤。将滤液在真空中浓缩并将残余物分配于水和乙酸乙酯之间。将有机相经硫酸钠干燥并蒸发。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,以得到作为棕色固体的(6-氨基-2,3-二氟-苯基)-甲醇;HPLC/MS 0.99 min (A), [M+H]+ 160。
1H NMR (400 MHz, DMSO-d6) δ 7.01 (dt, J = 10.6, 9.0 Hz, 1H), 6.42(ddd, J = 8.9, 4.1, 1.9 Hz, 1H), 5.13 (s, 2H), 5.07 (t, J = 5.5 Hz, 1H), 4.47(dd, J = 5.5, 2.3 Hz, 2H)。
向(6-氨基-2,3-二氟-苯基)-甲醇(565 mg, 3.56 mmol)于二氯甲烷(8 ml)中的溶液中添加二氧化锰(620 mg, 7.13 mmol),并将反应混合物在80℃下搅拌3小时。使反应混合物达到室温并经硅藻土过滤。将滤液蒸发,以得到作为棕色固体的6-氨基-2,3-二氟-苯甲醛;HPLC/MS 1.44 min (A), [M+H]+ 158,
1H NMR (400 MHz, DMSO-d6) δ 10.16 (d, J = 0.5 Hz, 1H), 7.44 (dt, J =10.5, 9.3 Hz, 1H), 7.34 (s, 2H), 6.57 (dddd, J = 9.4, 3.8, 2.0, 0.7 Hz, 1H)。
类似地制备以下化合物
2-氨基-4,6-二氟-苯甲醛,暗红色固体; HPLC/MS 1.47 min (A), [M+H]+ 158;
1H NMR (400 MHz, DMSO-d6) δ 10.08 (d, J = 0.6 Hz, 1H), 7.73 (s, 2H), 6.42– 6.34 (m, 2H)。
2-氨基-4,5-二氟-苯甲醛,暗棕色残余物; UPLC/MS 0.65 min, [M+H]+ 158。
1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.66 (dd, J = 11.0, 9.1 Hz,1H), 7.23 (s, 2H), 6.70 (dd, J = 13.2, 6.7 Hz, 1H)。
2-氨基-4-三氟甲基-苯甲醛,浅橙色固体; UPLC/MS 1.05 min, [M+H]+ 190。
1H NMR (500 MHz, DMSO-d6) δ 9.95 (d, J = 0.6 Hz, 1H), 7.79 (d, J = 8.1Hz, 1H), 7.40 (s, 2H), 7.13 (s, 1H), 6.90 (dd, J = 8.1, 1.7 Hz, 1H)。
2-氨基-5-氟-4-甲氧基-苯甲醛,米黄色固体; HPLC/MS 1.31 min (A), [M+H]+170。
实施例1
6-氟-3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A1”)
向3-乙炔基-6-氟-1H-喹啉-2-酮(46.8 mg, 0.25 mmol)、硫酸铜(II)五水合物(4.0mg, 0.03 mmol)和(2R)-2-[(2R)-3,4-二羟基-5-氧代-2H-呋喃-2-基]-2-羟基-乙醇钠水合物(5.4 mg, 0.03 mmol)于DMF (0.5 ml)中的悬浮液中添加(4-叠氮基-苯基)-吗啉-4-基-甲酮(65.0 mg, 0.28 mmol)。将反应混合物加热至110℃并在该温度下搅拌22小时。使反应混合物达到室温。添加水并将所得沉淀滤出,用水洗涤并干燥。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,以得到作为灰白色粉末的6-氟-3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮;HPLC/MS 1.44 min (A), [M+H]+420。
1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H),8.10 (d, J = 8.5 Hz, 2H), 7.80 (dd, J = 9.3, 2.7 Hz, 1H), 7.65 (d, J = 8.5Hz, 2H), 7.47 (dd, J = 9.0, 2.7 Hz, 1H), 7.45 – 7.39 (m, 1H), 3.75 – 3.35 (m,8H)。
类似地制备以下化合物:
3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A2”)
米黄色固体, HPLC/MS 1.27 min (B), [M+H]+ 402; 1H NMR (400 MHz, DMSO-d6) δ12.21 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H), 8.11 (d, J = 8.2 Hz, 2H), 7.92 (d,J = 7.9 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.42 (d,J = 8.3 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 3.75 – 3.35 (m, 8H)。
N,N-二甲基-4-[4-(2-氧代-1,2-二氢-[1,8]萘啶-3-基)-[1,2,3]三唑-1-基]-苯甲酰胺 (“A3”)
米黄色粉末; 1H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 9.28 (s, 1H), 8.87(s, 1H), 8.59 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 8.1 Hz, 2H),7.66 (d, J = 8.1 Hz, 2H), 7.34 (t, J = 6.3 Hz, 1H), 3.02 (s, 3H), 3.00 (s,3H)。
N,N-二甲基-4-[4-(2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰胺 (“A4”)
浅黄色固体, HPLC/MS 1.28 min (B), [M+H]+ 360; 1H NMR (400 MHz, DMSO-d6) δ12.22 (s, 1H), 9.26 (s, 1H), 8.84 (s, 1H), 8.14 – 8.04 (m, 2H), 7.91 (dd, J =7.9, 1.4 Hz, 1H), 7.68 – 7.62 (m, 2H), 7.56 (ddd, J = 8.5, 7.1, 1.4 Hz, 1H),7.41 (d, J = 8.1 Hz, 1H), 7.26 (ddd, J = 8.1, 7.2, 1.1 Hz, 1H), 3.02 (s, 4H),2.97 (s, 3H)。
3-[1-(4-二甲基氨基甲基-苯基)-1H-[1,2,3]三唑-4-基]-1H-[1,8]萘啶-2-酮(“A5”)
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.25 (br s, 1H), 8.83 (br s, 1H), 8.57(br s, 1H), 8.31 (d, 1H), 8.08 (d, 2H), 7.70 (d, 2H), 7.27 (br s, 1H), 4.34(s, 2H), 2.74 (s, 6H)。
3-(1-苯基-1H-[1,2,3]三唑-4-基)-1H-[1,8]萘啶-2-酮 (“A6”)
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.22 (br s, 1H), 8.85 (br s, 1H), 8.57(brs, 1H), 8.35 (d, 1H), 7.98 (d, 1H), 7.59 (m, 2H), 7.50 (m, 2H), 7.30 (brs, 1H)。
3-[1-(4-羟基甲基-苯基)-1H-[1,2,3]三唑-4-基]-1H-[1,8]萘啶-2-酮 (“A7”)
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.20 (br s, 1H), 8.81 (br s, 1H), 8.55(br s, 1H), 8.30 (d, 1H), 7.80 (d, 1H), 5.70 (s, 2H), 7.47 (d, 2H), 7.27 (d,1H), 4.53 (s, 2H)。
N-(2-羟基-乙基)-4-[4-(2-氧代-1,2-二氢-[1,8]萘啶-3-基)-[1,2,3]三唑-1-基]-苯甲酰胺 (“A8”)
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.31 (br s, 1H), 8.87 (br s, 1H), 8.57(br s, 1H), 8.36 (d, 1H), 8.13 (dd, 4H), 7.31 (br s, 1H), 3.51(m, 2H), 3.37(m, 2H)。
N-(2-甲氧基-乙基)-4-[4-(2-氧代-1,2-二氢-[1,8]萘啶-3-基)-[1,2,3]三唑-1-基]-苯甲酰胺 (“A9”)
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.29 (br s, 1H), 8.83 (br s, 1H), 8.55(br s, 1H), 8.30 (br s, 1H),8.05 (br s, 4H), 7.83 (br s, 0.5H), 7.54 (br s,0.5H), 7.26 ( br s, 1H), 3.44 (s, 4H), 3.23 (s, 3H)。
3-[1-(4-甲氧基-苯基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮 (“A10”)
黄色-棕色固体; HPLC/MS 1.43 min (B), [M+H]+ 319; 1H NMR (400 MHz, DMSO-d6)δ 12.19 (s, 1H), 9.09 (s, 1H), 8.82 (s, 1H), 7.95 – 7.86 (m, 3H), 7.55 (ddd,J = 8.5, 7.1, 1.4 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.25 (ddd, J = 8.2, 7.2,1.1 Hz, 1H), 7.19 – 7.11 (m, 2H), 3.85 (s, 3H)。
4-[4-(6-氯-2-氧代-1,2-二氢-[1,8]萘啶-3-基)-[1,2,3]三唑-1-基]-N,N-二甲基-苯甲酰胺 (“A11”)
浅棕色固体; HPLC/MS 1.31 min (B), [M+H]+ 395; 1H NMR (500 MHz, DMSO-d6) δ12.78 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H), 8.60 (d, J = 2.5 Hz, 1H), 8.55 (d,J = 2.5 Hz, 1H), 8.08 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 3.02 (s,3H), 2.97 (s, 3H)。
3-[1-(4-氟-苯基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮 (“A12”)
浅黄色固体; HPLC/MS 1.44 min (B), [M+H]+ 307; 1H NMR (400 MHz, DMSO-d6) δ12.20 (s, 1H), 9.19 (s, 1H), 8.83 (s, 1H), 8.12 – 8.02 (m, 2H), 7.90 (dd, J =7.9, 1.4 Hz, 1H), 7.56 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H), 7.51 – 7.43 (m, 2H),7.40 (dd, J = 8.2, 1.0 Hz, 1H), 7.25 (ddd, J = 8.1, 7.2, 1.1 Hz, 1H)。
3-[1-(2-氟-苯基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮 (“A13”)
浅黄色固体; HPLC/MS 1.43 min (B), [M+H]+ 307; 1H NMR (400 MHz, DMSO-d6) δ12.20 (s, 1H), 9.06 (d, J = 2.4 Hz, 1H), 8.85 (s, 1H), 7.95 (td, J = 7.9, 1.6Hz, 1H), 7.91 (dd, J = 8.0, 1.4 Hz, 1H), 7.68 – 7.52 (m, 3H), 7.51 – 7.44 (m,1H), 7.41 (dd, J = 8.2, 1.0 Hz, 1H), 7.26 (ddd, J = 8.1, 7.2, 1.1 Hz, 1H)。
3-{1-[4-(2-吡咯烷-1-基-乙氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A14”)
浅棕色晶体; HPLC/MS 1.13 min (B), [M+H]+ 402; 1H NMR (500 MHz, DMSO-d6) δ12.17 (s, 1H), 9.08 (s, 1H), 8.81 (s, 1H), 7.91 – 7.86 (m, 3H), 7.55 (ddd, J= 8.4, 7.1, 1.4 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.28 – 7.22 (m, 1H), 7.19– 7.11 (m, 2H), 4.16 (t, J = 5.9 Hz, 2H), 2.82 (t, J = 5.8 Hz, 2H), 2.56-2.52(m, 3H), 1.72 – 1.68 (m, 4H)。
N-(1-甲基-哌啶-4-基甲基)-4-[4-(2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰胺 (“A15”)
棕色固体; HPLC/MS 1.50 min (B), [M+H]+ 443; 1H NMR (500 MHz, DMSO-d6) δ12.21 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H), 8.63 (t, J = 5.8 Hz, 1H), 8.13 (d,J = 8.7 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H), 7.91 (dd, J = 8.0, 1.3 Hz, 1H),7.56 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.26 (t, J =7.7 Hz, 1H), 3.19 (t, J = 6.3 Hz, 2H), 2.84 – 2.74 (m, 2H), 2.19 (s, 3H),2.06 – 1.73 (m, 2H), 1.75 – 1.64 (m, 2H), 1.62 – 1.50 (m, 1H), 1.32 – 1.13(m, 2H)。
4-[4-(6-甲氧基-2-氧代-1,2-二氢-[1,8]萘啶-3-基)-[1,2,3]三唑-1-基]-N,N-二甲基-苯甲酰胺 (“A16”)
黄色固体; HPLC/MS 1.23 min (B), [M+H]+ 391; 1H NMR (500 MHz, DMSO-d6) δ12.51 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H), 8.36 (d, J = 3.0 Hz, 1H), 8.13 –8.06 (m, 2H), 8.03 (d, J = 3.0 Hz, 1H), 7.71 – 7.62 (m, 2H), 3.91 (s, 3H),3.03 (s, 3H), 2.98 (s, 3H)。
4-[4-(2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-吡啶-2-甲酸甲基酯(“A17”)
棕色固体; HPLC/MS 1.30 min (B), [M+H]+ 348; 1H NMR (400 MHz, DMSO-d6) δ12.23 (s, 1H), 9.52 (s, 1H), 8.91 (d, J = 5.3 Hz, 1H), 8.87 (s, 1H), 8.66 (d,J = 2.1 Hz, 1H), 8.38 (dd, J = 5.3, 2.2 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H),7.57 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.26 (t, J =7.4 Hz, 1H), 3.96 (s, 3H)。
4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-N,N-二甲基-苯甲酰胺 (“A18”)
浅黄色固体; HPLC/MS 1.31 min (B), [M+H]+ 378; 1H NMR (400 MHz, DMSO-d6) δ12.28 (s, 1H), 9.29 (s, 1H), 8.86 (s, 1H), 8.14 – 8.07 (m, 2H), 7.81 (dd, J =9.2, 2.6 Hz, 1H), 7.70 – 7.63 (m, 2H), 7.52 – 7.40 (m, 2H), 3.03 (s, 3H),2.99 (s, 3H)。
N-(2-羟基-乙基)-4-[4-(2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰胺 (“A19”)
浅棕色晶体; HPLC/MS 1.20 min (B), [M+H]+ 376; 1H NMR (400 MHz, DMSO-d6) δ12.20 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H), 8.60 (t, J = 5.6 Hz, 1H), 8.14 (d,J = 8.8 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 7.1 Hz, 0H), 7.56(ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.30 – 7.21 (m,1H), 4.73 (t, J = 5.6 Hz, 1H), 3.55 (q, J = 6.0 Hz, 2H), 3.37 (q, J = 6.0 Hz,2H)。
3-[1-(1H-吲哚-5-基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮 (“A20”)
棕色固体; HPLC/MS 1.38 min (B), [M+H]+ 328; 1H NMR (400 MHz, DMSO-d6) δ12.19 (s, 1H), 11.43 (s, 1H), 9.09 (s, 1H), 8.83 (s, 1H), 8.11 (s, 1H), 7.91(d, J = 7.9 Hz, 1H), 7.70 – 7.50 (m, 4H), 7.41 (d, J = 8.2 Hz, 1H), 7.26 (t,J = 7.5 Hz, 1H), 6.60 (s, 1H)。
N-(2-吗啉-4-基-乙基)-4-[4-(2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰胺 (“A21”)
浅棕色粉末; HPLC/MS 1.10 min (B), [M+H]+ 445; 1H NMR (500 MHz, DMSO-d6) δ12.21 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H), 8.58 (t, J = 5.7 Hz, 1H), 8.20 –8.11 (m, 2H), 8.11 – 8.02 (m, 2H), 7.91 (dd, J = 8.0, 1.4 Hz, 1H), 7.56 (ddd,J = 8.4, 7.1, 1.4 Hz, 1H), 7.41 (d, J = 8.2 Hz, 0H), 7.26 (ddd, J = 8.1, 7.2,1.1 Hz, 1H), 3.60 – 3.56 (m, 4H), 3.43 (q, J = 6.8 Hz, 2H), 2.52 – 2.48 (m,2H), 2.47 – 2.39 (m, 4H)。
4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-N-(1-甲基-哌啶-4-基甲基)-苯甲酰胺 (“A22”)
红色-棕色固体; HPLC/MS 1.12 min (B), [M+H]+ 461; 1H NMR (400 MHz, DMSO-d6)δ 12.28 (s, 1H), 9.31 (s, 1H), 8.85 (s, 1H), 8.62 (t, J = 5.8 Hz, 1H), 8.13(d, J = 8.8 Hz, 2H), 8.07 (d, J = 8.8 Hz, 2H), 7.80 (dd, J = 9.2, 2.6 Hz,1H), 7.53 – 7.34 (m, 2H), 3.18 (t, J = 6.3 Hz, 2H), 2.81 – 2.71 (m, 2H), 2.15(s, 3H), 1.93 – 1.75 (m, 2H), 1.71 – 1.61 (m, 2H), 1.60 – 1.48 (m, 1H), 1.26- 1.14 (m, 2H)。
3-[4-(2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酸甲酯 (“A23”)
浅棕色固体; HPLC/MS 1.45 min (B), [M+H]+ 347; 1H NMR (400 MHz, DMSO-d6) δ12.21 (s, 1H), 9.31 (s, 1H), 8.85 (s, 1H), 8.50 (t, J = 2.0 Hz, 1H), 8.32(dd, J = 8.1, 1.4 Hz, 1H), 8.08 (dt, J = 7.8, 1.3 Hz, 1H), 7.91 (dd, J = 8.0,1.3 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.56 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H),7.41 (d, J = 8.2 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 3.94 (s, 3H)。
3-[1-(3-甲氧基-苯基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮 (“A24”)
黄色固体; HPLC/MS 1.45 min (B), [M+H]+ 319; 1H NMR (400 MHz, DMSO-d6) δ12.17 (s, 1H), 9.22 (s, 1H), 8.82 (s, 1H), 7.90 (dd, J = 8.1, 1.4 Hz, 1H),7.60 – 7.48 (m, 4H), 7.43 – 7.38 (m, 1H), 7.25 (ddd, J = 8.1, 7.2, 1.1 Hz,1H), 7.08 (ddd, J = 8.1, 2.4, 1.2 Hz, 1H), 3.89 (s, 3H)。
3-{1-[4-(3-氧代-吗啉-4-基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A25”)
白色固体; HPLC/MS 1.27 min (B), [M+H]+ 388; 1H NMR (400 MHz, DMSO-d6) δ12.20 (s, 1H), 9.23 (s, 1H), 8.85 (s, 1H), 8.11 – 8.03 (m, 2H), 7.95 – 7.88(m, 1H), 7.74 – 7.65 (m, 2H), 7.57 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.42 (d,J = 8.2 Hz, 1H), 7.32 – 7.22 (m, 1H), 4.27 (s, 2H), 4.01 – 4.05 (m, 2H), 3.87– 3.82 (m, 2H)。
3-{1-[4-(2-吗啉-4-基-乙氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A26”)
米黄色固体; HPLC/MS 1.08 min (B), [M+H]+ 418; 1H NMR (400 MHz, DMSO-d6) δ12.17 (s, 1H), 9.09 (s, 1H), 8.82 (s, 1H), 7.92 – 7.87 (m, 3H), 7.56 (ddd, J= 8.4, 7.2, 1.4 Hz, 1H), 7.45 – 7.38 (m, 1H), 7.32 – 7.24 (m, 1H), 7.22 –7.13 (m, 2H), 4.20 (t, J = 5.7 Hz, 2H), 3.65 – 3.57 (m, 4H), 2.75 (t, J = 5.7Hz, 2H), 2.52 -2.49 (m, 4H)。
3-(1-苯基-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A27”)
黄色晶体; HPLC/MS 1.43 min (B), [M+H]+ 289; 1H NMR (500 MHz, DMSO-d6) δ12.19 (s, 1H), 9.19 (s, 1H), 8.83 (s, 1H), 8.03 – 7.97 (m, 2H), 7.90 (dd, J =7.9, 1.3 Hz, 1H), 7.67 – 7.59 (m, 2H), 7.59 – 7.49 (m, 2H), 7.43 – 7.39 (m,1H), 7.26 (ddd, J = 8.1, 7.2, 1.1 Hz, 1H)。
3-[1-(3H-苯并咪唑-5-基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮 (“A28”)
米黄色固体; HPLC/MS 1.09 min (B), [M+H]+ 329; 1H NMR (400 MHz, DMSO-d6,TFA-d1) δ 9.67 (s, 1H), 9.32 (s, 1H), 8.82 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H),8.21 (dd, J = 8.9, 2.0 Hz, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.82 (dd, J = 8.0,1.3 Hz, 1H), 7.49 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H),7.27 – 7.12 (m, 1H)。
3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,7]萘啶-2-酮(“A29”)
米黄色固体; HPLC/MS 1.11 min (B), [M+H]+ 403; 1H NMR (400 MHz, DMSO-d6) δ12.47 (s, 1H), 9.37 (s, 1H), 8.88 (s, 1H), 8.85 (bs, 1H), 8.48 (bs, 1H), 8.17– 8.06 (m, 2H), 7.91 (b, 1H), 7.75 – 7.60 (m, 2H), 3.80 – 3.35 (m, 8H)。
7-甲基-3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,8]萘啶-2-酮 (“A30”)
棕色固体; HPLC/MS 1.24 min (B), [M+H]+ 417; 1H NMR (500 MHz, DMSO-d6) δ12.46 (s, 1H), 9.24 (s, 1H), 8.82 (s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.13 –8.05 (m, 2H), 7.96 (s, 1H), 7.71 – 7.61 (m, 2H), 7.22 (d, J = 7.9 Hz, 1H),3.64 (bs, 4H), 2.51 (bs, 4H), 1.25 (s, 3H)。
6-氟-3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,8]萘啶-2-酮 (“A31”)
棕色固体, HPLC/MS 1.24 min (B), [M+H]+ 421; 1H NMR (400 MHz, DMSO-d6) δ12.73 (s, 1H), 9.31 (s, 1H), 8.88 (s, 1H), 8.63 (d, J = 2.9 Hz, 1H), 8.36(dd, J = 8.7, 3.0 Hz, 1H), 8.17 – 8.04 (m, 2H), 7.77 – 7.55 (m, 2H), 3.75 –3.40 (m, 8H)。
3-{1-[3-氟-4-(3-氧代-吗啉-4-基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A32”)
米黄色粉末, HPLC/MS 1.42 min (A), [M+H]+ 406; 1H NMR (400 MHz, DMSO-d6) δ12.21 (s, 1H), 9.32 (s, 1H), 8.84 (s, 1H), 8.12 (dd, J = 11.0, 2.4 Hz, 1H),8.04 – 7.95 (m, 1H), 7.90 (dd, J = 8.0, 1.4 Hz, 1H), 7.73 (t, J = 8.4 Hz,1H), 7.56 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.26(td, J = 7.6, 1.1 Hz, 1H), 4.28 (s, 2H), 4.05 – 4.00 (m, 2H), 3.81 – 3.65 (m,2H)。
6-氟-3-{1-[3-氟-4-(3-氧代-吗啉-4-基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A33”)
米黄色粉末, HPLC/MS 1.47 min (A), [M+H]+ 424; 1H NMR (400 MHz, DMSO-d6) δ12.28 (s, 1H), 9.34 (s, 1H), 8.85 (s, 1H), 8.13 (dd, J = 11.0, 2.4 Hz, 1H),8.01 – 7.95 (m, 1H), 7.80 (dd, J = 9.3, 2.7 Hz, 1H), 7.73 (t, J = 8.4 Hz,1H), 7.52 – 7.38 (m, 2H), 4.28 (s, 2H), 4.08 – 3.99 (m, 2H), 3.90 – 3.66 (m,2H)。
3-{1-[6-(3-氧代-吗啉-4-基)-吡啶-3-基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A34”)
米黄色固体, HPLC/MS 1.41 min (A), [M+H]+ 389; 1H NMR (400 MHz, DMSO-d6) δ12.21 (s, 1H), 9.32 (s, 1H), 9.11 (d, J = 2.7 Hz, 1H), 8.86 (s, 1H), 8.50(dd, J = 9.1, 2.8 Hz, 1H), 8.31 (d, J = 9.0 Hz, 1H), 7.95 – 7.90 (m, 1H),7.57 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.31 – 7.24(m, 1H), 4.33 (s, 2H), 4.05 (s, 4H)。
3-{1-[2-甲基-4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A35”)
米黄色固体, HPLC/MS 1.40 min (A), [M+H]+ 416; 1H NMR (300 MHz, DMSO-d6) δ12.16 (s, 1H), 8.92 (s, 1H), 8.84 (s, 1H), 7.89 (dd, J = 8.0, 1.4 Hz, 1H),7.61 (d, J = 8.1 Hz, 1H), 7.59 – 7.52 (m, 2H), 7.46 (dd, J = 8.1, 1.9 Hz,1H), 7.40 (d, J = 8.4 Hz, 1H), 7.26 (ddd, J = 8.1, 7.2, 1.2 Hz, 1H), 3.75 –3.35 (m, 8H), 2.26 (s, 3H)。
3-{1-[4-(1-羟基-1-甲基-乙基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A36”)
浅棕色固体, HPLC/MS 1.47 min (A), [M+H]+ 347; 1H NMR (400 MHz, DMSO-d6) δ12.18 (s, 1H), 9.15 (s, 1H), 8.82 (s, 1H), 7.93 – 7.88 (m, 3H), 7.73 – 7.66(m, 2H), 7.55 (ddd, J = 8.5, 7.1, 1.4 Hz, 1H), 7.41 (dd, J = 8.2, 1.0 Hz,1H), 7.25 (ddd, J = 8.1, 7.2, 1.1 Hz, 1H), 5.17 (s, 1H), 1.49 (s, 6H)。
3-{1-[3-氟-4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A37”)
黄色固体, HPLC/MS 1.45 min (A), [M+H]+ 420; 1H NMR (400 MHz, DMSO-d6) δ12.22 (s, 1H), 9.35 (s, 1H), 8.86 (s, 1H), 8.12 (dd, J = 10.4, 2.0 Hz, 1H),8.02 (dd, J = 8.3, 2.0 Hz, 1H), 7.92 (dd, J = 8.1, 1.4 Hz, 1H), 7.68 (dd, J =8.3, 7.4 Hz, 1H), 7.58 (ddd, J = 8.5, 7.1, 1.4 Hz, 1H), 7.42 (d, J = 8.2 Hz,1H), 7.27 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 3.69 (s, 4H), 3.61 – 3.56 (m, 2H),3.35 – 3-30 (m, 2H)。
3-[1-(3,4,5-三甲氧基-苯基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮 (“A38”)
米黄色固体, HPLC/MS 1.57 min (A), [M+H]+ 379; 1H NMR (400 MHz, DMSO-d6) δ12.18 (s, 1H), 9.27 (s, 1H), 8.83 (s, 1H), 7.91 (dd, J = 8.0, 1.4 Hz, 1H),7.56 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.31 (s, 2H),7.26 (ddd, J = 8.2, 7.2, 1.1 Hz, 1H), 3.93 (s, 6H), 3.75 (s, 3H)。
2-氟-N-甲基-4-[4-(2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰胺 (“A39”)
米黄色固体, HPLC/MS 1.42 min (A), [M+H]+ 364; 1H NMR (500 MHz, DMSO-d6) δ12.23 (s, 1H), 9.36 (s, 1H), 8.86 (s, 1H), 8.42 – 8.35 (m, 1H), 8.11 (dd, J =11.3, 2.1 Hz, 1H), 8.00 (dd, J = 8.4, 2.1 Hz, 1H), 7.92 (dd, J = 8.0, 1.3 Hz,1H), 7.86 (t, J = 8.1 Hz, 1H), 7.57 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.42 (d,J = 8.2 Hz, 1H), 7.33 – 7.23 (m, 1H), 2.83 (d, J = 4.6 Hz, 3H)。
3-{1-[3-甲基-4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A40”)
黄色粉末, HPLC/MS 1.43 min (A), [M+H]+ 416; 1H NMR (400 MHz, DMSO-d6) δ12.21 (s, 1H), 9.25 (s, 1H), 8.85 (s, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.93 –7.89 (m, 2H), 7.57 (ddd, J = 8.5, 7.1, 1.4 Hz, 1H), 7.46 – 7.40 (m, 2H), 7.27(ddd, J = 8.1, 7.2, 1.1 Hz, 1H), 3.70 (s, 4H), 3.55 (s, 2H), 3.21 (s, 2H),2.37 (s, 3H)。
实施例2
3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,6]萘啶-2-酮(“A41”)
向4-氨基-吡啶-3-甲醛 (61.1 mg, 0.50 mmol), {1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸 (158 mg, 0.50 mmol)和[二甲基氨基-([1,2,3]三唑并[4,5-b]吡啶-3-基氧基)-亚甲基]-二甲基-六氟磷酸铵(HATU; 380 mg, 1.0 mmol)于DMF (1.3ml)中的溶液中添加N-乙基二异丙胺(257 µl, 1.5 mmol),并将反应混合物在室温下搅拌17小时。将水添加至反应混合物中。将所得沉淀滤出,干燥并在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,以得到作为米黄色固体的3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,6]萘啶-2-酮;HPLC/MS 1.02 min (A), [M+H]+ 403。
1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.28 (s, 1H), 9.10 (s, 1H),8.93 (s, 1H), 8.52 (d, J = 5.7 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.67 (d, J= 8.6 Hz, 2H), 7.30 (d, J = 5.7 Hz, 1H), 3.35 - 3.75 (m, 8H)。
类似地制备以下化合物:
N,N-二甲基-4-[4-(2-氧代-1,2-二氢-[1,7]萘啶-3-基)-[1,2,3]三唑-1-基]-苯甲酰胺 (“A42”)
棕色粉末, MS-ESI: [M+H]+ 361。
3-(1-苯基-1H-吡唑-4-基)-1H-[1,8]萘啶-2-酮 (“A43”)
棕色粉末, HPLC/MS 1.34 min (B), [M+H]+ 289; 1H NMR (400 MHz, DMSO-d6) δ12.40 (s, 1H), 9.12 (s, 1H), 8.51 (dd, J = 4.7, 1.7 Hz, 1H), 8.44 (s, 1H),8.42 (s, 1H), 8.11 (dd, J = 7.8, 1.8 Hz, 1H), 7.96 – 7.82 (m, 2H), 7.63 –7.50 (m, 2H), 7.40 – 7.33 (m, 1H), 7.29 (dd, J = 7.7, 4.7 Hz, 1H)。
3-(1-苯基-1H-吡唑-4-基)-1H-[1,7]萘啶-2-酮 (“A44”)
棕色粉末, HPLC/MS 1.21 min (B), [M+H]+ 289; 1H NMR (400 MHz, DMSO-d6) δ12.27 (s, 1H), 9.19 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 8.35(d, J = 5.2 Hz, 1H), 7.97 – 7.80 (m, 2H), 7.60 (d, J = 5.0 Hz, 1H), 7.58 –7.50 (m, 2H), 7.42 – 7.26 (m, 1H)。
3-[1-(4-氟-苯基)-1H-[1,2,3]三唑-4-基]-1H-[1,6]萘啶-2-酮 (“A45”)
棕色固体, HPLC/MS 1.09 min (B), [M+H]+ 308; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.44 (s, 1H), 9.17 (s, 1H), 9.07 (s, 1H), 8.61 (d, J = 6.7 Hz, 1H),8.02 – 7.92 (m, 2H), 7.70 (d, J = 6.7 Hz, 1H), 7.31 (t, J = 8.7 Hz, 2H)。
3-(1-苯基-1H-吡唑-4-基)-1H-[1,6]萘啶-2-酮 (“A46”)
米黄色粉末, HPLC/MS 1.06 min (B), [M+H]+ 289; 1H NMR (400 MHz, DMSO-d6) δ12.27 (s, 1H), 9.11 (s, 1H), 8.86 (d, J = 0.7 Hz, 1H), 8.50 (s, 1H), 8.46 (d,J = 5.5 Hz, 2H), 7.91 – 7.85 (m, 2H), 7.57 – 7.50 (m, 2H), 7.39 – 7.32 (m,1H), 7.25 (d, J = 5.7 Hz, 1H)。
3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,8]萘啶-2-酮“A47”)
米黄色固体, HPLC/MS 1.27 min (A), [M+H]+ 403; 1H NMR (400 MHz, DMSO-d6) δ12.58 (s, 1H), 9.28 (s, 1H), 8.87 (s, 1H), 8.59 (dd, J = 4.7, 1.8 Hz, 1H),8.38 (dd, J = 7.8, 1.8 Hz, 1H), 8.11 (d, J = 8.6 Hz, 2H), 7.78 – 7.60 (m,2H), 7.34 (dd, J = 7.8, 4.7 Hz, 1H), 3.76 – 3.36 (m, 8H)。
5-氟-3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A48”)
米黄色固体, HPLC/MS 1.45 min (A), [M+H]+ 420; 1H NMR (400 MHz, DMSO-d6) δ12.44 (s, 1H), 9.28 (s, 1H), 8.82 (s, 1H), 8.10 (d, J = 8.6 Hz, 2H), 7.66 (d,J = 8.6 Hz, 2H), 7.57 (td, J = 8.2, 6.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H),7.18 – 7.05 (m, 1H), 3.75 – 3.35 (m, 8H)。
3-{1-[4-(3-氧代-吗啉-4-基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,7]萘啶-2-酮 (“A49”)
米黄色固体, HPLC/MS 1.45 min (A), [M+H]+ 420; 1H NMR (400 MHz, DMSO-d6) δ12.44 (s, 1H), 9.28 (s, 1H), 8.82 (s, 1H), 8.10 (d, J = 8.6 Hz, 2H), 7.66 (d,J = 8.6 Hz, 2H), 7.57 (td, J = 8.2, 6.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H),7.18 – 7.05 (m, 1H), 3.75 – 3.35 (m, 8H)。
实施例3
3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A50”)
将4-{4-[4-(2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰基}-哌嗪-1-甲酸叔丁酯(43 mg, 0.09 mmol; 类似于实施例1合成)于盐酸于二氧杂环己烷中的4 M溶液(0.5 ml)中的悬浮液加热至80℃并在该温度下在封闭的反应小瓶中搅拌1小时。使反应混合物达到室温。将固体滤出并用THF洗涤。将残余物用碳酸钠水溶液处理。将固体滤出,用水和乙醇洗涤并在真空下干燥,以得到作为浅灰色粉末的3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮;HPLC/MS 1.07 min (B), [M+H]+ 401。
1H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 9.26 (s, 1H), 8.84 (s, 1H),8.08 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H),7.56 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H),3.65 – 3.35 (m, 4H), 2.8 – 2.6 (m, 4H)。
类似地制备以下化合物:
4-[4-(2-氧代-1,2-二氢-[1,8]萘啶-3-基)-[1,2,3]三唑-1-基]-N-哌啶-4-基-苯甲酰胺 (“A51”)
三氟乙酸盐: 1H NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 1H), 9.33 (br s,1H), 8.87 (br s, 1H), 8.64-8.58 (m, 3H), 8.34 (m, 2H), 8.17(d, 2H), 8.10 (d,2H), 7.34 (br s, 1H), 4.09 (br s, 1H), 3.06 (m, 2H), 2.02 (d, 2H), 1.78-1.70(m, 2H),
3-[1-(4-哌嗪-1-基-苯基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮 (“A52”)
浅棕色晶体; HPLC/MS 1.10 min (B), [M+H]+ 373; 1H NMR (500 MHz, DMSO-d6,TFA-d1) δ 9.11 (s, 1H), 8.83 (s, 1H), 7.91 – 7.86 (m, 3H), 7.55 (ddd, J =8.5, 7.1, 1.4 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.28 – 7.19 (m, 3H), 3.53 –3.49 (m, 4H), 3.34 – 3.30 (m, 4H)。
6-氟-3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A53”)
盐酸盐: 浅棕色固体; HPLC/MS 1.07 min (B), [M+H]+ 419; 1H NMR (500 MHz,DMSO-d6) δ 12.30 (s, 1H), 9.31 (s, 1H), 9.22 (bs, 2H), 8.86 (s, 1H), 8.13 (d,J = 8.6 Hz, 2H), 7.81 (dd, J = 9.2, 2.7 Hz, 1H), 7.72 (d, J = 8.6 Hz, 2H),7.51 – 7.38 (m, 2H), 3.72 (bs, 4H), 3.20 (bs, 4H)。
3-[1-(2-哌嗪-1-基-嘧啶-5-基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮(“A54”)
盐酸盐: 棕色固体; HPLC/MS 1.14 min (A), [M+H]+ 375; 1H NMR (400 MHz,DMSO-d 6) δ 12.20 (s, 1H), 9.18 (m, 3H), 8.99 (s, 2H), 8.82 (s, 1H), 7.90 (d,J = 7.8 Hz, 1H), 7.56 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.41 (d, J = 8.2 Hz,1H), 7.30 – 7.21 (m, 1H), 4.06 (t, J = 5.3 Hz, 4H), 3.26 – 3.19 (m, 4H)。
3-[1-(4-[1,4]二氮杂环庚烷-1-基-苯基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮 (“A55”)
棕色固体; HPLC/MS 1.22 min (A), [M+H]+ 387; 1H NMR (500 MHz, DMSO-d6) δ12.13 (s, 1H), 8.95 (s, 1H), 8.79 (s, 1H), 7.88 (dd, J = 8.0, 1.4 Hz, 1H),7.68 (d, J = 9.1 Hz, 2H), 7.54 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H), 7.40 (dd, J =8.2, 1.0 Hz, 1H), 7.24 (ddd, J = 8.1, 7.2, 1.1 Hz, 1H), 6.85 (d, J = 9.1 Hz,2H), 3.60 (t, J = 6.1 Hz, 2H), 3.52 (t, J = 5.3 Hz, 2H), 2.95 – 2.85 (m, 2H),2.70 – 2.61 (m, 2H), 1.80 (p, J = 6.1 Hz, 2H)。
实施例4
6-氟-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A56”)
向4-{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰基}-哌嗪-1-甲酸叔丁酯(52 mg, 0.10 mmol; 类似于实施例1制备)于甲酸(0.5 ml)中的溶液中添加甲醛 (37%水溶液, 22.5 µl, 0.30 mmol),并将反应混合物在80℃下搅拌1小时。将反应混合物蒸发,并将残余物通过制备型HPLC纯化,以得到作为白色粉末的6-氟-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮;HPLC/MS 1.07 min(B), [M+H]+ 433。
1H NMR (500 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.29 (s, 1H), 8.86 (s, 1H),8.10 (d, J = 8.5 Hz, 2H), 7.81 (dd, J = 9.2, 2.7 Hz, 1H), 7.66 – 7.60 (m,2H), 7.50 – 7.40 (m, 2H), 3.78 – 3.50 (m, 4H), 2.47 – 2.26 (m, 4H), 2.22 (s,3H)。
类似地制备以下化合物:
3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A57”)
白色粉末; HPLC/MS 1.08 min (B), [M+H]+ 415; 1H NMR (400 MHz, DMSO-d6) δ12.20 (s, 1H), 9.89 (s, 1H), 9.28 (s, 1H), 8.84 (s, 1H), 8.28 – 8.07 (m, 2H),7.90 (d, J = 7.3 Hz, 1H), 7.72 – 7.68 (m, 2H), 7.56 (ddd, J = 8.5, 7.1, 1.4Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.26 (ddd, J = 8.1, 7.2, 1.1 Hz, 1H), 3.7– 3.0 (m, 8H), 2.81 (s, 3H)。
N-(1-甲基-哌啶-4-基)-4-[4-(2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰胺 (“A58”)
甲酸盐: 白色固体; HPLC/MS 1.10 min (B), [M+H]+ 429; 1H NMR (500 MHz,DMSO-d6) δ 12.22 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H), 8.43 (d, J = 7.7 Hz,1H), 8.20 (s, 2H), 8.14 (d, J = 8.7 Hz, 2H), 8.11 – 8.07 (m, 2H), 7.92 (dd, J= 8.0, 1.3 Hz, 1H), 7.57 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.42 (d, J = 8.3Hz, 1H), 7.27 (td, J = 7.6, 1.1 Hz, 1H), 3.79 (tdt, J = 11.7, 8.3, 4.4 Hz,1H), 2.87 – 2.78 (m, 2H), 2.21 (s, 3H), 2.02 (td, J = 11.8, 2.5 Hz, 2H), 1.88– 1.77 (m, 2H), 1.63 (qd, J = 12.1, 3.8 Hz, 2H)。
N-甲基-N-(1-甲基-哌啶-4-基)-4-[4-(2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰胺 (“A59”)
米黄色固体; HPLC/MS 1.09 min (B), [M+H]+ 443; 1H NMR (400 MHz, DMSO-d6) δ12.20 (s, 1H), 9.26 (s, 1H), 8.84 (s, 1H), 8.12 – 8.04 (m, 2H), 7.90 (dd, J =8.0, 1.4 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.56 (ddd, J = 8.5, 7.1, 1.4 Hz,1H), 7.41 (d, J = 8.2 Hz, 1H), 7.32 – 7.22 (m, 1H), 4.4 - 4.2 (m, 1H), 2.85(s, 6H), 2.25 – 2.05 (m, 4H), 1.90 – 1.78 (m, 2H), 1.67 – 1.58 (m, 2H)。
3-{1-[4-(1-甲基-哌啶-4-基甲氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A60”)
白色固体; HPLC/MS 1.12 min (B), [M+H]+ 416; 1H NMR (400 MHz, DMSO-d6) δ12.16 (s, 1H), 9.08 (s, 1H), 8.81 (s, 1H), 7.91 – 7.84 (m, 3H), 7.55 (ddd, J= 8.5, 7.1, 1.4 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.33 – 7.22 (m, 1H), 7.19– 7.07 (m, 2H), 3.92 (d, J = 6.0 Hz, 2H), 2.82 – 2.76 (m, 2H), 2.17 (s, 3H),1.92 - 1.84 (m, 2H), 1.81 – 1.70 (m, 3H), 1.45 – 1.26 (m, 2H)。
3-{1-[4-(4-二甲基氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A61”)
浅黄色固体; HPLC/MS 1.06 min (B), [M+H]+ 443; 1H NMR (400 MHz, DMSO-d6) δ12.19 (s, 1H), 9.25 (s, 1H), 8.84 (s, 1H), 8.11 – 8.03 (m, 2H), 7.90 (dd, J =8.0, 1.4 Hz, 1H), 7.66 – 7.60 (m, 2H), 7.56 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H),7.41 (d, J = 8.3 Hz, 1H), 7.26 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 4.45 (bs,1H), 3.64 (bs, 1H), 3.06 (bs, 1H), 2.89 (bs, 1H), 2.36 (tt, J = 11.0, 3.6 Hz,1H), 2.19 (s, 6H), 1.90 – 1.65 (m, 2H), 1.45 – 1.30 (m, 2H)。
3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,6]萘啶-2-酮 (“A62”)
白色固体; HPLC/MS 0.87 min (A), [M+H]+ 416; 1H NMR (400 MHz, DMSO-d6) δ12.48 (s, 1H), 9.27 (s, 1H), 9.09 (bs, 1H), 8.92 (s, 1H), 8.52 (bs, 1H), 8.15– 8.04 (m, 2H), 7.70 – 7.56 (m, 2H), 7.29 (d, J = 5.6 Hz, 1H), 3.72 – 3.54(m, 4H), 2.44 – 2.26 (m, 4H), 2.21 (s, 3H)。
3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,7]萘啶-2-酮 (“A63”)
浅棕色固体; HPLC/MS 0.98 min (A), [M+H]+ 416; 1H NMR (300 MHz, DMSO-d6) δ12.47 (bs, 1H), 9.34 (s, 1H), 8.86 (s, 1H), 8.75 (s, 1H), 8.39 (d, J = 5.2Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 5.2 Hz, 1H), 7.63 (d, J = 8.6Hz, 1H), 3.5 – 3.2 (m, 4H), 2.42 – 2.29 (m, 4H), 2.21 (s, 3H)。
3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,8]萘啶-2-酮 (“A64”)
米黄色固体; HPLC/MS 1.06 min (A), [M+H]+ 416; 1H NMR (400 MHz, DMSO-d6) δ12.59 (s, 1H), 9.28 (s, 1H), 8.87 (s, 1H), 8.59 (dd, J = 4.7, 1.8 Hz, 1H),8.38 (dd, J = 7.9, 1.8 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.5Hz, 1H), 7.34 (dd, J = 7.7, 4.7 Hz, 1H), 3.7 – 3.3 (m, 4H), 2.45 – 2.25 (m,4H), 2.23 (s, 3H)。
7-甲基-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,8]萘啶-2-酮 (“A65”)
浅黄色固体; HPLC/MS 1.11 min (A), [M+H]+ 430。
3-{1-[2-(4-甲基-哌嗪-1-基)-嘧啶-5-基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A66”)
米黄色固体; HPLC/MS 1.16 min (A), [M+H]+ 389; 1H NMR (400 MHz, DMSO-d6) δ12.17 (s, 1H), 9.12 (s, 1H), 8.88 (s, 2H), 8.81 (s, 1H), 7.89 (dd, J = 8.1,1.3 Hz, 1H), 7.55 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H),7.28 – 7.23 (m, 1H), 3.88 – 3.77 (m, 4H), 2.45 – 2.35 (m, 4H), 2.24 (s, 3H)。
6-氟-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,8]萘啶-2-酮 (“A67”)
白色固体; HPLC/MS 1.09 min (A), [M+H]+ 434; 1H NMR (400 MHz, DMSO-d6) δ12.73 (s, 1H), 9.30 (s, 1H), 8.87 (s, 1H), 8.61 (d, J = 2.9 Hz, 1H), 8.35(dd, J = 8.7, 2.9 Hz, 1H), 8.09 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.5 Hz,2H), 3.74 – 3.30 (m, 4H), 2.44 – 2.26 (m, 4H), 2.21 (s, 3H)。
3-{1-[4-(4-甲基-2-氧代-哌嗪-1-基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A68”)
白色固体; HPLC/MS 1.19 min (A), [M+H]+ 401; 1H NMR (400 MHz, DMSO-d6) δ12.18 (s, 1H), 9.21 (s, 1H), 8.83 (s, 1H), 8.02 (d, J = 8.9 Hz, 2H), 7.90(dd, J = 8.1, 1.4 Hz, 1H), 7.67 – 7.58 (m, 2H), 7.55 (ddd, J = 8.5, 7.1, 1.4Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.25 (td, J = 7.5, 1.1 Hz, 1H), 3.76 –3.72 (m, 2H), 3.16 (s, 2H), 2.84 – 2.70 (m, 2H), 2.31 (s, 3H)。
3-{1-[4-(4-甲基-[1,4]二氮杂环庚烷-1-基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A69”)
米黄色固体; HPLC/MS 1.23 min (A), [M+H]+ 401; 1H NMR (400 MHz, DMSO-d6) δ12.15 (s, 1H), 8.97 (s, 1H), 8.77 (s, 1H), 7.86 (dd, J = 8.0, 1.4 Hz, 1H),7.68 (d, J = 9.1 Hz, 2H), 7.52 (ddd, J = 8.5, 7.1, 1.4 Hz, 1H), 7.39 (d, J =8.2 Hz, 1H), 7.22 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 6.85 (d, J = 9.2 Hz, 2H),3.65 – 3.55 (m, 2H), 3.50 (t, J = 6.2 Hz, 2H), 2.70 – 2.58 (m, 2H), 2.49 –2.45 (m, 2H), 2.27 (s, 3H), 1.92 (p, J = 5.9 Hz, 2H)。
6-氟-3-{1-[4-(4-甲基-哌嗪-1-基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A70”)
灰白色固体; HPLC/MS 1.24 min (A), [M+H]+ 405; 1H NMR (500 MHz, DMSO-d6) δ12.23 (s, 1H), 9.05 (s, 1H), 8.81 (s, 1H), 7.92 – 7.66 (m, 3H), 7.49 – 7.37(m, 2H), 7.11 (d, J = 9.2 Hz, 2H), 3.24 (t, J = 5.0 Hz, 4H), 2.47 (t, J = 5.0Hz, 4H), 2.24 (s, 3H)。
6-氟-3-{1-[4-(4-甲基-2-氧代-哌嗪-1-基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A71”)
米黄色固体; HPLC/MS 1.19 min (A), [M+H]+ 419; 1H NMR (500 MHz, DMSO-d6) δ12.26 (s, 1H), 9.23 (s, 1H), 8.84 (s, 1H), 8.03 (d, J = 8.9 Hz, 2H), 7.80(dd, J = 9.2, 2.6 Hz, 1H), 7.60 (d, J = 8.9 Hz, 2H), 7.48 – 7.40 (m, 2H),3.74 (t, J = 5.3 Hz, 2H), 3.16 (s, 2H), 2.76 (t, J = 5.4 Hz, 2H), 2.31 (s,3H)。
3-(1-{4-[2-(4-甲基-哌嗪-1-基)-乙氧基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A72”)
白色固体; HPLC/MS 1.20 min (A), [M+H]+ 431; 1H NMR (400 MHz, DMSO-d6) δ12.16 (s, 1H), 9.08 (s, 1H), 8.81 (s, 1H), 7.92 – 7.85 (m, 3H), 7.55 (ddd, J= 8.4, 7.1, 1.4 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.25 (ddd, J = 8.1, 7.1,1.1 Hz, 1H), 7.20 – 7.12 (m, 2H), 4.16 (t, J = 5.8 Hz, 2H), 2.72 (t, J = 5.8Hz, 2H), 2.54 – 2.50 (m, 4H), 2.33 (bs, 4H), 2.15 (s, 3H)。
实施例5
3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-吡唑-4-基}-1H-喹啉-2-酮 (“A73”)和3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-吡唑-4-基}-1H-喹啉-2-酮 (“A74”)
a) 4-{4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷(dioxaborolan)-2-基)-吡唑-1-基]-苯甲酰基}-哌嗪-1-甲酸叔丁酯的合成
b) Suzuki反应 – 4-{4-[4-(2-氧代-1,2-二氢-喹啉-3-基)-吡唑-1-基]-苯甲酰基}-哌嗪-1-甲酸叔丁酯的合成
类似地制备3-(1-苯基-1H-吡唑-4-基)-1H-喹啉-2-酮 (“A75”):
白色粉末; HPLC/MS 1.45 min (B), [M+H]+ 288; 1H NMR (400 MHz, DMSO-d6) δ12.00 (s, 1H), 9.11 (s, 1H), 8.45 (s, 1H), 8.42 (s, 1H), 7.91 – 7.85 (m, 2H),7.68 (dd, J = 7.9, 1.3 Hz, 1H), 7.56 – 7.51 (m, 2H), 7.49 (ddd, J = 8.4, 7.1,1.5 Hz, 1H), 7.39 – 7.31 (m, 2H), 7.22 (ddd, J = 8.2, 7.2, 1.2 Hz, 1H)。
c) 3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-吡唑-4-基}-1H-喹啉-2-酮 (“A73”)和3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-吡唑-4-基}-1H-喹啉-2-酮 (“A74”)的合成
”A73”: 白色固体; HPLC/MS 1.06 min (B), [M+H]+ 400; 1H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 9.18 (s, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 8.18 (s, 1H),7.99 – 7.93 (m, 2H), 7.70 (dd, J = 8.0, 1.3 Hz, 1H), 7.59 – 7.54 (m, 2H),7.51 (ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.24 (ddd, J= 8.1, 7.2, 1.1 Hz, 1H), 3.46 (bs, 4H), 2.78 (bs, 4H)。
“A74” 甲酸盐: 白色固体; HPLC/MS 1.17 min (A), [M+H]+ 400; 1H NMR (700MHz, DMSO-d6) δ 12.05 (s, 1H), 9.19 (s, 1H), 8.50 (s, 1H), 8.45 (s, 1H), 8.00– 7.93 (m, 2H), 7.69 (dd, J = 8.0, 1.3 Hz, 1H), 7.60 – 7.53 (m, 2H), 7.53 –7.48 (m, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 3.65 (bs,2H), 3.40 (bs, 2H), 2.34 (bs, 4H), 2.21 (s, 3H)。
实施例6
3-{1-[3-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A76”)
a) 3-[4-(2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酸的合成
向3-[4-(2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酸甲酯(346 mg,1.0 mmol)于THF/水(1:1, 4 ml)中的悬浮液中添加氢氧化锂(211 mg, 8.8 mmol),并将反应混合物在65℃下搅拌2小时。在冷却至室温后,添加1 N盐酸水溶液,直至达到1的pH。将所得沉淀滤出,用水洗涤并在真空下干燥,以得到作为橄榄绿色固体的3-[4-(2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酸;HPLC/MS 1.31 min (B), [M+H]+ 333; 1HNMR (400 MHz, DMSO-d6) δ 13.40 (s, 1H), 12.22 (s, 1H), 9.29 (s, 1H), 8.85 (s,1H), 8.47 (d, J = 1.9 Hz, 1H), 8.31 – 8.24 (m, 2H), 8.06 (dt, J = 7.6, 1.3Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.56 (ddd, J =8.5, 7.1, 1.4 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.29 – 7.23 (m, 1H)。
类似地制备4-[4-(2-氧代-1,2-二氢-[1,8]萘啶-3-基)-[1,2,3]三唑-1-基]-苯甲酸 (“A77”)
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.31 (d, 1H), 8.86 (br s, 1H), 8.54-8.53 (m, 3H), 8.34 (dd, 2H), 8.16 (m, 4H), 7.30 (m, 1H)。
b) “A76”的合成
向3-[4-(2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酸(99.7 mg, 0.30mmol)、吗啉(26 µl, 0.39 mmol)和[二甲基氨基(三唑并[4,5-b]吡啶-3-基氧基)亚甲基]-二甲基-六氟磷酸铵(HATU; 114 mg, 0.30 mmol)于DMF (0.6 ml)中的溶液中添加乙基-二异丙基-胺(153 µl, 0.90 mmol)并将反应混合物在室温下搅拌16小时。将反应混合物用饱和Na2CO3水溶液和水处理。将所得沉淀滤出,用水洗涤并在真空下干燥,以得到作为灰白色固体的3-{1-[3-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮;HPLC/MS1.28 min (B), [M+H]+ 402。
1H NMR (500 MHz, DMSO-d6) δ 12.20 (s, 1H), 9.28 (s, 1H), 8.84 (s, 1H),8.11 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 8.05 (t, J = 1.9 Hz, 1H), 7.90 (dd, J =8.0, 1.3 Hz, 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.59 – 7.50 (m, 2H), 7.41 (d, J =8.2 Hz, 1H), 7.26 (td, J = 7.5, 1.1 Hz, 1H), 3.74 – 3.34 (m, 8H)。
实施例7
3-{1-[3-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A78”)和3-{1-[3-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A79”)
“A78”: 浅黄色固体; HPLC/MS 1.15 min (A), [M+H]+ 401。
1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 9.27 (s, 1H), 8.83 (s, 1H),8.12 – 8.05 (m, 1H), 8.01 (t, J = 1.8 Hz, 1H), 7.89 (dd, J = 8.0, 1.4 Hz,1H), 7.68 (t, J = 7.9 Hz, 1H), 7.55 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.49(dt, J = 7.7, 1.3 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.32 – 7.21 (m, 1H),3.58 (bs, 2H), 3.29 (bs, 2H), 2.81 – 2.62 (m, 4H)。
“A79”: 白色固体; HPLC/MS 1.15 min (A), [M+H]+ 415。
1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 9.27 (s, 1H), 8.83 (s, 1H),8.10 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 8.02 (t, J = 1.8 Hz, 1H), 7.90 (dd, J =8.0, 1.4 Hz, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.56 (ddd, J = 8.5, 7.1, 1.4 Hz,1H), 7.50 (dt, J = 7.7, 1.2 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.25 (ddd, J =8.2, 7.2, 1.1 Hz, 1H), 3.66 (bs, 2H), 3.38 (bs, 2H), 2.45 – 2.25 (m, 4), 2.21(s, 3H)。
实施例8
3-[1-(4-异丙烯基-苯基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮 (“A80”)和3-{1-[4-(1-甲磺酰基-1-甲基-乙基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A81”)
向3-{1-[4-(1-羟基-1-甲基-乙基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(97.0 mg, 0.28 mmol)于二氯甲烷(0.5 ml)中的溶液中添加甲烷亚磺酸钠(62.6 mg,0.61 mmol),随后添加三氟乙酸(176 µl, 2.28 mmol)于二氯甲烷(0.4 ml)中的溶液。将反应混合物在室温下搅拌19小时。将反应混合物用二氯甲烷和水稀释。将有机相分离并将有机相用水萃取两次。将合并的有机相经硫酸钠干燥并蒸发。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,以得到两种产物:
“A80”: 3-[1-(4-异丙烯基-苯基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮,白色晶体;HPLC/MS 1.80 min (A), [M+H]+ 329;
1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 9.20 (s, 1H), 8.83 (s, 1H),8.03 – 7.95 (m, 2H), 7.90 (dd, J = 8.0, 1.3 Hz, 1H), 7.78 – 7.70 (m, 2H),7.56 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.25 (ddd, J= 8.1, 7.1, 1.1 Hz, 1H), 5.56 (s, 1H), 5.23 – 5.20 (m, 1H), 2.18 (d, J = 1.1Hz, 3H)。
“A81”: 3-{1-[4-(1-甲磺酰基-1-甲基-乙基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮, 白色小板; HPLC/MS 1.50 min (A), [M+H]+ 409;
1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 9.24 (s, 1H), 8.83 (s, 1H),8.12 – 8.02 (m, 2H), 7.90 (dd, J = 8.1, 1.4 Hz, 1H), 7.87 – 7.81 (m, 2H),7.56 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.26 (ddd, J= 8.1, 7.2, 1.1 Hz, 1H), 2.77 (s, 3H), 1.83 (s, 6H)。
实施例9
7-氯-3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A82”)
向{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸(158 mg, 0.50 mmol)和2-氨基-4-氯苯甲醛(77.8 mg, 0.5 mmol)于乙酸酐(0.5 ml)中的悬浮液中添加三乙胺(277 µl, 2.0 mmol),并将反应混合物在室温下搅拌18小时。将反应混合物用乙酸乙酯稀释。将固体滤出并干燥。将残余物用水处理。将固体滤出,用水洗涤并在真空下干燥,以得到作为米黄色粉末的7-氯-3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮;HPLC/MS 1.53 min (A), [M+H]+ 436。
1H NMR (400 MHz, DMSO-d 6) δ 12.27 (s, 1H), 9.26 (s, 1H), 8.85 (s, 1H),8.15 – 8.04 (m, 2H), 7.95 (d, J = 8.5 Hz, 1H), 7.75 – 7.59 (m, 2H), 7.42 (d,J = 2.1 Hz, 1H), 7.30 (dd, J = 8.5, 2.0 Hz, 1H), 3.85 – 3.33 (m, 8H)。
类似地制备以下化合物:
7-氟-3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A83”)
灰白色晶体; HPLC/MS 1.44 min (A), [M+H]+ 420; 1H NMR (400 MHz, DMSO-d6) δ12.27 (s, 1H), 9.24 (s, 1H), 8.86 (s, 1H), 8.17 – 8.04 (m, 2H), 8.00 (dd, J =9.6, 6.1 Hz, 1H), 7.69 – 7.62 (m, 2H), 7.17 – 7.10 (m, 2H), 3.80 – 3.35 (m,8H)。
7-甲基-3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A84”)
米黄色固体; HPLC/MS 1.47 min (A), [M+H]+ 416; 1H NMR (500 MHz, DMSO-d6) δ12.13 (s, 1H), 9.24 (s, 1H), 8.80 (s, 1H), 8.13 – 8.07 (m, 2H), 7.79 (d, J =8.1 Hz, 1H), 7.70 – 7.63 (m, 2H), 7.20 (s, 1H), 7.11 (dd, J = 8.1, 1.5 Hz,1H), 3.75 – 3.35 (m, 8H), 2.43 (s, 3H)。
3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,5]萘啶-2-酮(“A85”)
浅黄色晶体; HPLC/MS 1.20 min (A), [M+H]+ 403; 1H NMR (700 MHz, DMSO-d6) δ12.40 (s, 1H), 9.34 (s, 1H), 8.76 (s, 1H), 8.58 (dd, J = 4.5, 1.4 Hz, 1H),8.11 (d, J = 8.6 Hz, 2H), 7.78 (dd, J = 8.3, 1.4 Hz, 1H), 7.66 (d, J = 8.5Hz, 2H), 7.58 (dd, J = 8.3, 4.4 Hz, 1H), 3.65 (bs, 4H), 3.40 (bs, 4H)。
6-氟-3-(1-{4-[4-(3-甲氧基-丙基)-哌嗪-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A86”)
米黄色固体; HPLC/MS 1.23 min (A), [M+H]+ 491; 1H NMR (400 MHz, DMSO-d6) δ12.27 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H), 8.08 (d, J = 8.6 Hz, 2H), 7.80(dd, J = 9.1, 2.6 Hz, 1H), 7.62 (d, J = 8.6 Hz, 2H), 7.50 – 7.37 (m, 2H),3.75 – 3.30 (m, 4H), 3.35 (t, J = 6.4 Hz, 2H), 3.22 (s, 3H), 2.47 – 2.32 (m,6H), 1.67 (p, J = 6.7 Hz, 2H)。
5-氟-3-(1-{4-[4-(3-甲氧基-丙基)-哌嗪-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A87”)
灰白色固体; HPLC/MS 1.25 min (A), [M+H]+ 491; 1H NMR (400 MHz, DMSO-d6) δ12.43 (s, 1H), 9.28 (s, 1H), 8.82 (s, 1H), 8.09 (d, J = 8.6 Hz, 2H), 7.62 (d,J = 8.6 Hz, 2H), 7.57 (td, J = 8.2, 6.1 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H),7.11 (ddd, J = 10.1, 8.1, 0.9 Hz, 1H), 3.70 – 3.30 (m, 4H), 3.35 (t, J = 6.4Hz, 2H), 3.22 (s, 3H), 2.40 (bs, 4H), 2.36 (t, J = 7.3 Hz, 2H), 1.78 – 1.57(m, 2H)。
6-氟-3-(1-{4-[4-(3-甲氧基-丙基)-哌嗪-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-[1,8]萘啶-2-酮 (“A88”)
米黄色固体; HPLC/MS 1.14 min (A), [M+H]+ 492; 1H NMR (400 MHz, DMSO-d6) δ12.70 (s, 1H), 9.29 (s, 1H), 8.86 (s, 1H), 8.61 (d, J = 2.9 Hz, 1H), 8.35(dd, J = 8.7, 3.0 Hz, 1H), 8.09 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz,2H), 3.75 – 3.30 (m, 4H), 3.35 (t, J = 6.4 Hz, 2H), 3.22 (s, 3H), 2.39 (bs, 4H) 2.36 (t, J = 7.3 Hz, 2H), 1.67 (p, J = 6.6 Hz, 2H)。
3-(1-{4-[4-(3-甲氧基-丙基)-哌嗪-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-[1,8]萘啶-2-酮 (“A89”)
白色固体; HPLC/MS 1.08 min (A), [M+H]+ 474; 1H NMR (500 MHz, DMSO-d6) δ12.58 (s, 1H), 9.27 (s, 1H), 8.86 (s, 1H), 8.57 (dd, J = 4.7, 1.8 Hz, 1H),8.36 (dd, J = 7.8, 1.8 Hz, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5Hz, 2H), 7.33 (dd, J = 7.7, 4.7 Hz, 1H), 3.70 – 3.32 (m, 4H), 3.35 (t, J =6.4 Hz, 2H), 3.22 (s, 3H), 2.40 (bs, 4H), 2.36 (t, J = 7.3 Hz, 2H), 1.67 (m,2H)。
5,7-二氟-3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A90”)
米黄色固体; HPLC/MS 1.51 min (A), [M+H]+ 438; 1H NMR (500 MHz, DMSO-d6) δ12.54 (s, 1H), 9.28 (s, 1H), 8.77 (s, 1H), 8.11 (d, J = 8.6 Hz, 2H), 7.67 (d,J = 8.6 Hz, 2H), 7.24 (td, J = 9.9, 2.4 Hz, 1H), 7.03 (dd, J = 9.9, 2.1 Hz,1H), 3.75 – 3.35 (m, 8H)。
7-溴-3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A91”)
米黄色固体; HPLC/MS 1.56 min (A), [M+H]+ 482; 1H NMR (400 MHz, DMSO-d6) δ12.27 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H), 8.15 – 8.07 (m, 2H), 7.89 (d, J =8.5 Hz, 1H), 7.72 – 7.63 (m, 2H), 7.59 (d, J = 1.9 Hz, 1H), 7.44 (dd, J =8.4, 1.9 Hz, 1H), 3.74 – 3.38 (m, 8H)。
6-氟-3-{1-[4-(4-甲基-3-氧代-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A92”)
灰白色粉末; UPLC/MS 0.62 min, [M+H]+ 447; 1H NMR (400 MHz, DMSO-d6) δ12.27 (s, 1H), 9.30 (s, 1H), 8.85 (s, 1H), 8.15 – 8.07 (m, 2H), 7.80 (dd, J =9.2, 2.7 Hz, 1H), 7.75 – 7.66 (m, 2H), 7.52 – 7.38 (m, 2H), 4.12 (bs, 2H),3.94 – 3.58 (m, 2H), 3.40 (t, J = 5.5 Hz, 2H), 2.89 (s, 3H)。
7-甲氧基-3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A93”)
米黄色粉末; UPLC/MS 0.66 min, [M+H]+ 432; 1H NMR (400 MHz, DMSO-d6) δ12.06 (s, 1H), 9.19 (s, 1H), 8.76 (s, 1H), 8.13 – 8.04 (m, 2H), 7.82 (d, J =8.3 Hz, 1H), 7.73 – 7.62 (m, 2H), 6.96 – 6.83 (m, 2H), 3.85 (s, 3H), 3.72 –3.38 (m, 8H)。
6-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-8H-吡啶并[2,3-d]嘧啶-7-酮 (“A94”)
黄色固体; HPLC/MS 1.15 min (A), [M+H]+ 404; 1H NMR (400 MHz, DMSO-d6) δ12.97 (s, 1H), 9.30 (s, 1H), 9.29 (s, 1H), 9.03 (s, 1H), 8.91 (s, 1H), 8.15 –8.10 (m, 2H), 7.71 – 7.66 (m, 3H), 3.64 (s, 16H)。
6-氟-3-{1-[3-(2-吗啉-4-基-乙氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A94a”)
浅米黄色固体; HPLC/MS 1.24 min (A), [M+H]+ 436; 1H NMR (400 MHz, DMSO-d6)δ 12.25 (s, 1H), 9.25 (s, 1H), 8.83 (s, 1H), 7.79 (dd, J = 9.2, 2.6 Hz, 1H),7.59 – 7.54 (m, 2H), 7.50 (t, J = 8.4 Hz, 1H), 7.46 – 7.39 (m, 2H), 7.08(ddd, J = 8.2, 2.4, 1.2 Hz, 1H), 4.24 (t, J = 5.7 Hz, 2H), 3.64 – 3.55 (m,4H), 2.74 (t, J = 5.7 Hz, 2H), 2.53 – 2.49 (m, 4H)。
5,7-二氟-3-{1-[4-(4-甲基-3-氧代-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A95”)
灰白色粉末; UPLC/MS 0.66 min, [M+H]+ 465; 1H NMR (400 MHz, DMSO-d6) δ12.50 (s, 1H), 9.28 (s, 1H), 8.75 (s, 1H), 8.27 – 8.03 (m, 2H), 7.81 – 7.59(m, 2H), 7.21 (td, J = 9.9, 2.4 Hz, 1H), 7.01 (dd, J = 9.9, 2.3 Hz, 1H), 4.13(bs, 2H), 3.94 – 3.60 (m, 2H), 3.44- 3.36 (m, 2H), 2.89 (s, 3H)。
6-氯-3-{1-[4-(4-甲基-3-氧代-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A96”)
灰白色粉末; UPLC/MS 0.67 min, [M+H]+ 463; 1H NMR (400 MHz, DMSO-d6) δ12.32 (s, 1H), 9.29 (s, 1H), 8.84 (s, 1H), 8.16 – 8.08 (m, 2H), 8.05 (d, J =2.3 Hz, 1H), 7.74 – 7.67 (m, 2H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H), 7.41 (d, J= 8.8 Hz, 1H), 4.13 (bs, 2H), 3.94 – 3.60 (m, 2H), 3.40 (t, J = 5.4 Hz, 2H),2.89 (s, 3H)。
7-氯-3-{1-[4-(4-甲基-3-氧代-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A97”)
灰白色粉末; UPLC/MS 0.67 min, [M+H]+ 463; 1H NMR (400 MHz, DMSO-d6) δ12.28 (s, 1H), 9.27 (s, 1H), 8.86 (s, 1H), 8.16 – 8.08 (m, 2H), 7.95 (d, J =8.5 Hz, 1H), 7.77 – 7.66 (m, 2H), 7.42 (d, J = 2.0 Hz, 1H), 7.30 (dd, J =8.4, 2.1 Hz, 1H), 4.12 (bs, 2H), 3.94 – 3.60 (m, 2H), 3.40 (t, J = 5.5 Hz,2H), 2.89 (s, 3H)。
6-氟-3-{1-[4-(2-氧代-噁唑烷-3-基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A98”)
灰白色粉末; HPLC/MS 1.51 min (A), [M+H]+ 392; 1H NMR (400 MHz, DMSO-d6) δ12.26 (s, 1H), 9.19 (s, 1H), 8.83 (s, 1H), 8.23 – 7.95 (m, 2H), 7.90 – 7.77(m, 3H), 7.51 – 7.34 (m, 2H), 4.49 (m, 2H), 4.15 (m, 2H)。
3-{1-[4-(1,1-二氧代-1l6-异噻唑烷-2-基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A99”)
淡棕色粉末; HPLC/MS 1.53 min (A), [M+H]+ 426; 1H NMR (500 MHz, DMSO-d6) δ12.26 (s, 1H), 9.18 (s, 1H), 8.84 (s, 1H), 8.13 – 7.94 (m, 2H), 7.80 (dd, J =9.2, 2.7 Hz, 1H), 7.48 – 7.37 (m, 4H), 3.84 (t, J = 6.5 Hz, 2H), 3.58 (t, J =7.4 Hz, 2H), 2.45 (p, J = 6.8 Hz, 2H)。
3-{1-[4-([1,3']联吡咯烷基-1'-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A100”)
米黄色固体; HPLC/MS 1.20 min (A), [M+H]+ 473; 1H NMR (700 MHz, DMSO-d6,TFA-d1) δ 9.32 (s, 1H), 8.87 (s, 1H), 8.12 (d, J = 8.3 Hz, 2H), 7.81 (d, J =8.1 Hz, 2H), 7.65 (dd, J = 9.0, 2.8 Hz, 1H), 7.50 (dd, J = 9.0, 4.7 Hz, 1H),7.37 (td, J = 8.7, 2.8 Hz, 1H), 4.18 – 3.46 (m, 7H), 3.33 – 3.01 (m, 2H),2.51 – 1.95 (m, 6H)。
3-(1-{4-[2-(4-乙酰基-哌嗪-1-基)-乙氧基]-苯基}-1H-[1,2,3]三唑-4-基)-6-氟-1H-喹啉-2-酮 (“A100a”)
棕色固体; HPLC/MS 1.21 min (A), [M+H]+ 477; 1H NMR (500 MHz, DMSO-d6) δ12.24 (s, 1H), 9.11 (s, 1H), 8.82 (s, 1H), 7.93 – 7.85 (m, 2H), 7.79 (dd, J =9.2, 2.7 Hz, 1H), 7.49 – 7.38 (m, 2H), 7.21 – 7.12 (m, 2H), 4.19 (t, J = 5.7Hz, 2H), 3.50 – 3.39 (m, 4H), 2.77 (t, J = 5.7 Hz, 2H), 2.52 (m, 2H), 2.45(m, 2H), 1.99 (s, 3H)。
3-(1-{4-[2-(4-乙酰基-哌嗪-1-基)-乙氧基]-苯基}-1H-[1,2,3]三唑-4-基)-6,7-二氟-1H-喹啉-2-酮 (“A101”)
棕色固体; HPLC/MS 1.25 min (A), [M+H]+ 495; 1H NMR (500 MHz, DMSO-d6) δ12.29 (s, 1H), 9.08 (s, 1H), 8.81 (s, 1H), 8.07 (dd, J = 11.0, 8.6 Hz, 1H),7.96 – 7.82 (m, 2H), 7.32 (dd, J = 11.4, 7.0 Hz, 1H), 7.24 – 7.10 (m, 2H),4.19 (t, J = 5.7 Hz, 2H), 3.50 – 3.38 (m, 4H), 2.77 (t, J = 5.7 Hz, 2H), 2.52(m, 2H), 2.45 (t, J = 5.2 Hz, 2H), 1.99 (s, 3H)。
乙酸 1-{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰基}-哌啶-4-基酯 (“A102”)
米黄色固体; HPLC/MS 1.55 min (A), [M+H]+ 476。
乙酸 1-{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰基}-哌啶-3-基酯 (“A103”)
灰白色固体; HPLC/MS 1.55 min (A), [M+H]+ 476。
3-{1-[4-([1,3']联吡咯烷基-1'-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 (“A104”)
棕色固体; HPLC/MS 1.24 min (A), [M+H]+ 491。
3-{1-[4-([1,3']联吡咯烷基-1'-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-5,7-二氟-1H-喹啉-2-酮 (“A105”)
米黄色固体; HPLC/MS 1.25 min (A), [M+H]+ 491。
6-氟-3-{1-[4-(3-甲氧基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A106”)
浅棕色固体; HPLC/MS 1.52 min (A), [M+H]+ 448。
3-{1-[3-([1,3']联吡咯烷基-1'-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A107”)
棕色固体; HPLC/MS 1.20 min (A), [M+H]+ 473。
3-{1-[3-([1,3']联吡咯烷基-1'-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 (“A108”)
棕色固体; HPLC/MS 1.24 min (A), [M+H]+ 491。
6,7-二氟-3-{1-[4-(3-甲氧基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A109”)
棕色固体; HPLC/MS 1.56 min (A), [M+H]+ 466。
6-氟-3-{1-[4-(4-甲基-5-氧代-[1,4]二氮杂环庚烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A110”)
棕色固体; UPLC/MS 0.89 min, [M+H]+ 461。
6-氟-3-{1-[4-((R)-3-甲氧基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A111”)
灰白色固体; UPLC/MS 0.94 min, [M+H]+ 434。
6-氟-3-{1-[4-((S)-3-甲氧基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A112”)
灰白色固体; UPLC/MS 0.94 min, [M+H]+ 434。
6,7-二氟-3-{1-[4-((R)-3-甲氧基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A113”)
灰白色固体; UPLC/MS 0.96 min, [M+H]+ 452。
6,7-二氟-3-{1-[4-((S)-3-甲氧基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A114”)
灰白色固体; UPLC/MS 0.96min, [M+H]+ 452。
3-{1-[4-(2-二甲基氨基-乙基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 (“A115”)
米黄色固体; UPLC/MS 0.48 min, [M+H]+ 396. 1H NMR (300 MHz, DMSO-d6) δ12.31 (s, 1H), 9.15 (s, 1H), 8.83 (s, 1H), 8.08 (dd, J = 11.1, 8.6 Hz, 1H),7.93 – 7.84 (m, 2H), 7.50 – 7.43 (m, 2H), 7.33 (dd, J = 11.5, 7.1 Hz, 1H),2.81 (t, J = 7.5 Hz, 2H), 2.53 (t, J = 7.5 Hz, 2H), 2.21 (s, 6H)。
6,7-二氟-3-{1-[4-(2-吡咯烷-1-基-乙基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A115a”)
米黄色固体; UPLC/MS 0.49 min, [M+H]+ 396. 1H NMR (300 MHz, DMSO-d6) δ12.31 (s, 1H), 9.15 (s, 1H), 8.83 (s, 1H), 8.08 (dd, J = 11.1, 8.6 Hz, 1H),7.89 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.33 (dd, J = 11.5, 7.1Hz, 1H), 2.81 (t, J = 7.5 Hz, 2H), 2.56 – 2.49 (m, 6H), 2.21 (s, 4H)。
3-{1-[4-(2-二乙基氨基-乙氧基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 (“A116”)
米黄色固体; HPLC/MS 1.31 min (A), [M+H]+ 440; 1H NMR (500 MHz, DMSO-d6) δ12.29 (s, 1H), 9.08 (s, 1H), 8.81 (s, 1H), 8.07 (dd, J = 11.0, 8.5 Hz, 1H),7.96 – 7.82 (m, 2H), 7.31 (dd, J = 11.4, 7.0 Hz, 1H), 7.19 – 7.07 (m, 2H),4.10 (t, J = 6.1 Hz, 2H), 2.81 (t, J = 6.1 Hz, 2H), 2.57 (q, J = 7.1 Hz, 4H),0.99 (t, J = 7.1 Hz, 6H)。
6,7-二氟-3-{1-[4-(2-吡咯烷-1-基-乙氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A186”)
米黄色固体; HPLC/MS 1.28 min (A), [M+H]+ 438; 1H NMR (500 MHz, DMSO-d6) δ12.29 (s, 1H), 9.08 (s, 1H), 8.81 (s, 1H), 8.06 (dd, J = 11.0, 8.6 Hz, 1H),7.87 (d, J = 9.0 Hz, 2H), 7.31 (dd, J = 11.4, 7.1 Hz, 1H), 7.15 (d, J = 9.0Hz, 2H), 4.16 (t, J = 5.9 Hz, 2H), 2.83 (t, J = 5.8 Hz, 2H), 2.58 – 2.53 (m,4H), 1.74 – 1.66 (m, 4H)。
N-{4-[4-(6,7-二氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯基}-N-甲基-乙酰胺 (“A352”)
HPLC/MS 1.50 min (A), [M+H]+ 396;
1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.24 (s, 1H), 8.84 (s, 1H),8.12 – 8.05 (m, 3H), 7.68 – 7.54 (m, 2H), 7.33 (dd, J = 11.5, 7.1 Hz, 1H),3.24 (bs, 3H), 1.90 (bs, 3H)。
N-{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯基}-N-甲基-乙酰胺 (“A353”)
HPLC/MS 1.45 min (A), [M+H]+ 378;
1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.26 (s, 1H), 8.84 (s, 1H),8.07 (d, J = 8.2 Hz, 2H), 7.80 (dd, J = 9.3, 2.6 Hz, 1H), 7.59 (d, J = 8.5Hz, 2H), 7.53 – 7.38 (m, 2H), 3.24 (bs, 3H), 1.90 (bs, 3H)。
6-氟-3-[1-(2-甲基-1-氧代-2,3-二氢-1H-异吲哚-5-基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮 (“A354”)
UPLC/MS 0.66 min, [M+H]+ 376;
1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 9.34 (s, 1H), 8.88 (s, 1H),8.31 (d, J = 1.9 Hz, 1H), 8.15 (dd, J = 8.2, 2.0 Hz, 1H), 7.87 (d, J = 8.2Hz, 1H), 7.81 (dd, J = 9.3, 2.7 Hz, 1H), 7.54 – 7.30 (m, 2H), 3.13 (s, 3H),2.55 (s, 2H)。
6-氟-3-{1-[4-((反)-3-甲氧基-环戊基氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A355”)
HPLC/MS 1.73 min (A), [M+H]+ 421;
1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 9.09 (s, 1H), 8.82 (s, 1H),7.92 – 7.83 (m, 2H), 7.79 (dd, J = 9.1, 2.6 Hz, 1H), 7.51 – 7.37 (m, 2H),7.15 – 7.00 (m, 2H), 4.85 (tt, J = 7.2, 3.4 Hz, 1H), 3.83 (p, J = 4.7 Hz,1H), 3.20 (s, 3H), 2.39 (dt, J = 14.1, 7.0 Hz, 1H), 2.07 – 1.96 (m, 1H), 1.90– 1.74 (m, 2H), 1.69 (dt, J = 14.4, 3.9 Hz, 1H)。
6-氯-3-{1-[4-((1S,3R)-3-甲氧基-环戊基氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A356”)
HPLC/MS 1.83 min (A), [M+H]+ 437;
1H NMR (500 MHz, DMSO-d6) δ 12.30 (s, 1H), 9.10 (s, 1H), 8.82 (s, 1H),8.05 (d, J = 2.4 Hz, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.58 (dd, J = 8.8, 2.4Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.19 – 6.97 (m, 2H), 4.86 (tt, J = 7.1,3.8 Hz, 1H), 3.84 (dq, J = 6.6, 4.7 Hz, 1H), 3.21 (s, 3H), 2.40 (dt, J =14.1, 7.0 Hz, 1H), 2.02 (dtd, J = 15.1, 7.6, 5.8 Hz, 1H), 1.89 – 1.74 (m,3H), 1.70 (dt, J = 14.4, 4.0 Hz, 1H)。
6-氟-3-[1-(4-甲氧基-苯基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮 (“A357”)
UPLC/MS 0.77 min, [M+H]+ 337;
1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 9.11 (s, 1H), 8.82 (s, 1H),8.09 – 7.86 (m, 2H), 7.79 (dd, J = 9.1, 2.5 Hz, 1H), 7.58 – 7.36 (m, 2H),7.23 – 7.01 (m, 2H), 3.86 (s, 3H)。
6-氟-3-{1-[4-((R)-3-甲氧基-吡咯烷-1-磺酰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A358”)
HPLC/MS 1.63 min (A), [M+H]+ 470;
1H NMR (700 MHz, DMSO-d 6) δ 12.33 (s, 1H), 9.40 (s, 1H), 8.88 (s, 1H),8.31 (d, J = 8.7 Hz, 2H), 8.13 – 7.97 (m, 2H), 7.82 (dd, J = 9.1, 2.8 Hz,1H), 7.47 (td, J = 8.8, 2.9 Hz, 1H), 7.43 (dd, J = 9.0, 4.8 Hz, 1H), 3.86(dq, J = 5.7, 3.0 Hz, 1H), 3.37 – 3.30 (m, 3H), 3.17 (td, J = 9.6, 7.2 Hz,1H), 3.04 (s, 3H), 1.92 – 1.72 (m, 2H)。
6-氯-3-{1-[4-((R)-3-甲氧基-吡咯烷-1-磺酰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A359”)
HPLC/MS 1.73 min (A), [M+H]+ 486;
1H NMR (400 MHz, DMSO-d 6) δ 12.35 (s, 1H), 9.38 (s, 1H), 8.86 (s, 1H),8.38 – 8.23 (m, 2H), 8.06 (d, J = 2.3 Hz, 1H), 8.05 – 7.97 (m, 2H), 7.60 (dd,J = 8.8, 2.3 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 3.87 (p, J = 3.2 Hz, 1H),3.38 – 3.30 (m, 3H), 3.18 (td, J = 9.4, 7.5 Hz, 1H), 1.89 – 1.70 (m, 2H)。
6-氟-3-{1-[4-((S)-3-甲氧基-吡咯烷-1-磺酰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A360”)
HPLC/MS 1.63 min (A), [M+H]+ 470;
1H NMR (700 MHz, DMSO-d 6) δ 12.33 (s, 1H), 9.40 (s, 1H), 8.88 (s, 1H),8.31 (d, J = 8.7 Hz, 2H), 8.13 – 7.97 (m, 2H), 7.82 (dd, J = 9.1, 2.8 Hz,1H), 7.47 (td, J = 8.8, 2.9 Hz, 1H), 7.43 (dd, J = 9.0, 4.8 Hz, 1H), 3.86(dq, J = 5.7, 3.0 Hz, 1H), 3.37 – 3.30 (m, 3H), 3.17 (td, J = 9.6, 7.2 Hz,1H), 3.04 (s, 3H), 1.92 – 1.72 (m, 2H)。
6-氯-3-{1-[4-((S)-3-甲氧基-吡咯烷-1-磺酰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A361”)
HPLC/MS 1.73 min (A), [M+H]+ 486;
1H NMR (400 MHz, DMSO-d 6) δ 12.35 (s, 1H), 9.38 (s, 1H), 8.86 (s, 1H),8.38 – 8.23 (m, 2H), 8.06 (d, J = 2.3 Hz, 1H), 8.05 – 7.97 (m, 2H), 7.60 (dd,J = 8.8, 2.3 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 3.87 (p, J = 3.2 Hz, 1H),3.38 – 3.30 (m, 3H), 3.18 (td, J = 9.4, 7.5 Hz, 1H), 1.89 – 1.70 (m, 2H)。
6-氟-3-{1-[4-((1S,2S)-2-甲氧基-环戊基氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A362”)
HPLC/MS 1.83 min (A), [M+H]+ 421;
1H NMR (500 MHz, DMSO-d 6) δ 12.29 (s, 1H), 9.13 (s, 1H), 8.84 (s, 1H),8.03 – 7.86 (m, 2H), 7.81 (dd, J = 9.2, 2.8 Hz, 1H), 7.46 (td, J = 8.8, 2.8Hz, 1H), 7.42 (dd, J = 9.0, 4.9 Hz, 1H), 7.20 – 7.13 (m, 2H), 4.74 (dt, J =6.0, 2.9 Hz, 1H), 3.85 – 3.81 (m, 1H), 3.30 (s, 3H), 2.19 – 2.07 (m, 1H),2.03 – 1.90 (m, 1H), 1.75 – 1.61 (m, 4H)。
6-氯-3-[1-(4-环戊基氧基-苯基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮(“A363”)
UPLC/MS 0.97 min, [M+H]+ 407;
1H NMR (500 MHz, DMSO-d 6) δ 12.34 (s, 1H), 9.11 (s, 1H), 8.82 (s, 1H),8.06 (d, J = 2.4 Hz, 1H), 7.95 – 7.82 (m, 2H), 7.59 (dd, J = 8.8, 2.4 Hz,1H), 7.40 (d, J = 8.8 Hz, 1H), 7.16 – 7.06 (m, 2H), 4.95 – 4.90 (m, 1H), 2.07– 1.85 (m, 2H), 1.84 – 1.68 (m, 4H), 1.67 – 1.57 (m, 2H)。
3-[1-(4-环戊基氧基-苯基)-1H-[1,2,3]三唑-4-基]-6-氟-1H-喹啉-2-酮(“A364”)
UPLC/MS 0.91 min, [M+H]+ 391;
1H NMR (500 MHz, DMSO-d 6) δ 12.29 (s, 1H), 9.11 (s, 1H), 8.83 (s, 1H),7.91 – 7.85 (m, 2H), 7.81 (dd, J = 9.3, 2.8 Hz, 1H), 7.46 (td, J = 8.8, 2.8Hz, 1H), 7.42 (dd, J = 9.1, 4.9 Hz, 1H), 7.15 – 7.09 (m, 2H), 4.95 – 4.90 (m,1H), 2.02 – 1.92 (m, 2H), 1.80 – 1.68 (m, 4H), 1.68 – 1.56 (m, 2H)。
6-氟-3-{1-[4-(四氢-呋喃-3-基氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A365”)
UPLC/MS 0.77 min, [M+H]+ 393;
1H NMR (500 MHz, DMSO-d6) δ 12.29 (s, 1H), 9.13 (s, 1H), 8.83 (s, 1H),8.04 – 7.87 (m, 2H), 7.81 (dd, J = 9.2, 2.8 Hz, 1H), 7.46 (td, J = 8.8, 2.8Hz, 1H), 7.42 (dd, J = 9.0, 4.9 Hz, 1H), 7.18 – 7.11 (m, 2H), 5.15 (ddt, J =6.2, 3.9, 1.7 Hz, 1H), 3.93 (dd, J = 10.2, 4.5 Hz, 1H), 3.91 – 3.82 (m, 2H),3.79 (td, J = 8.4, 4.6 Hz, 1H), 2.28 (dtd, J = 16.4, 8.2, 6.2 Hz, 1H), 2.06 –1.94 (m, 1H)。
6-氯-3-{1-[4-(四氢-呋喃-3-基氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A366”)
UPLC/MS 0.82 min, [M+H]+ 409;
1H NMR (500 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.12 (s, 1H), 8.82 (s, 1H),8.06 (d, J = 2.3 Hz, 1H), 7.98 – 7.83 (m, 2H), 7.59 (dd, J = 8.8, 2.4 Hz,1H), 7.40 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 9.0 Hz, 2H), 5.14 (ddd, J = 6.2,4.2, 1.9 Hz, 1H), 3.93 (dd, J = 10.2, 4.5 Hz, 1H), 3.91 – 3.82 (m, 2H), 3.79(td, J = 8.4, 4.6 Hz, 1H), 2.28 (dtd, J = 14.4, 8.2, 6.2 Hz, 1H), 2.07 – 1.95(m, 1H)。
实施例10
7-氟-3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A117”)和7-氟-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A118”)
向4-[4-(4-羧基甲基-[1,2,3]三唑-1-基)-苯甲酰基]-哌嗪-1-甲酸叔丁酯(291 mg,0.70 mmol)和2-氨基-4-氟-苯甲醛(97.4 mg, 0.7 mmol)于乙酸酐(1.17 ml)中的悬浮液中添加三乙胺(388 µl, 2.80 mmol),并将反应混合物在室温下搅拌16小时。将反应混合物用二氯甲烷和水处理。将有机相分离并将水相用二氯甲烷萃取。将合并的有机相经硫酸钠干燥并蒸发。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,以得到作为米黄色固体的4-{4-[4-(7-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰基}-哌嗪-1-甲酸叔丁酯;HPLC/MS 1.70 min (A), [M+H]+ 519。
实施例10a
“A117”的合成
将4-{4-[4-(7-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰基}-哌嗪-1-甲酸叔丁酯(83.0 mg, 0.16 mmol)于盐酸于二氧杂环己烷中的4 M溶液(362 µl)中的悬浮液加热至70℃并在该温度下在封闭的反应小瓶中搅拌4小时。使反应混合物达到室温并在真空下浓缩。将残余物用饱和Na2CO3溶液处理并将混合物蒸发。将固体残余物用二氯甲烷和甲醇的混合物萃取。将萃取溶液蒸发,并将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,以得到作为灰白色固体的7-氟-3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮;HPLC/MS 1.18 min (A), [M+H]+ 419。
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.26 (s, 1H), 8.87 (s, 1H), 8.11(d, J = 8.6 Hz, 2H), 7.90 (dd, J = 8.8, 6.0 Hz, 1H), 7.74 (d, J = 8.6 Hz,2H), 7.22 (dd, J = 10.2, 2.5 Hz, 1H), 7.06 (td, J = 8.8, 2.5 Hz, 1H), 3.83(bs, 4H), 3.27 (bs, 4H)。
类似地制备以下化合物:
5-氟-3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A119”)
米黄色固体; HPLC/MS 1.20 min (A), [M+H]+ 419; 1H NMR (400 MHz, DMSO-d6,TFA-d1) δ 9.17 (s, 1H), 8.84 (s, 1H), 8.00 (d, J = 8.7 Hz, 2H), 7.62 (d, J =8.6 Hz, 2H), 7.40 (td, J = 8.2, 5.9 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 6.95 –6.86 (m, 1H), 3.72 (bs, 4H), 3.15 (bs, 4H)。
8-氟-3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A120”)
米黄色固体; HPLC/MS 1.17 min (A), [M+H]+ 419; 1H NMR (500 MHz, DMSO-d6,TFA-d1) δ 9.27 (s, 1H), 8.90 (d, J = 1.5 Hz, 1H), 8.09 (d, J = 8.6 Hz, 2H),7.73 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 7.8 Hz, 1H), 7.37 (ddd, J = 11.0, 8.1,1.2 Hz, 1H), 7.23 (td, J = 8.0, 4.8 Hz, 1H), 3.85 (bs, 4H), 3.27 (bs, 4H)。
3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,8]萘啶-2-酮(“A121”)
米黄色固体; HPLC/MS 1.05 min (A), [M+H]+ 402; 1H NMR (400 MHz, DMSO-d6,TFA-d1) δ 9.21 (s, 1H), 8.83 (s, 1H), 8.52 (dd, J = 4.9, 1.8 Hz, 1H), 8.31(dd, J = 7.9, 1.7 Hz, 1H), 8.04 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.6 Hz,2H), 7.27 (dd, J = 7.8, 4.9 Hz, 1H), 3.72 (bs, 4H), 3.18 (bs, 4H)。
6-氟-3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,8]萘啶-2-酮 (“A122”)
米黄色固体; HPLC/MS 1.08 min (A), [M+H]+ 420; 1H NMR (400 MHz, DMSO-d6) δ12.74 (s, 1H), 9.32 (s, 1H), 9.30 (bs, 1H), 8.88 (s, 1H), 8.63 (d, J = 2.7Hz, 1H), 8.37 (dd, J = 8.7, 2.9 Hz, 1H), 8.13 (d, J = 8.6 Hz, 2H), 7.73 (d, J= 8.6 Hz, 2H), 3.75 (bs, 4H), 3.19 (s, 4H)。
6-氯-3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A123”)
灰白色固体; HPLC/MS 1.26 min (A), [M+H]+ 435; 1H NMR (400 MHz, DMSO-d6) δ12.35 (s, 1H), 9.30 (s, 1H), 9.28 (bs, 1H), 8.85 (s, 1H), 8.13 (d, J = 8.5Hz, 2H), 8.06 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.60 (dd, J =8.7, 2.4 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 3.75 (bs, 4H), 3.20 (s, 4H)。
3-[1-(4-[1,4]二氮杂环庚烷-1-基-苯基)-1H-[1,2,3]三唑-4-基]-6-氟-1H-[1,8]萘啶-2-酮 (“A124”)
绿色-棕色固体; HPLC/MS 1.17 min (A), [M+H]+ 406; 1H NMR (400 MHz, DMSO-d6,TFA-d1) δ 9.05 (s, 1H), 8.84 (s, 1H), 8.52 (d, J = 2.9 Hz, 1H), 8.18 (dd, J =8.5, 2.9 Hz, 1H), 7.78 (d, J = 9.1 Hz, 2H), 6.99 (d, J = 9.2 Hz, 2H), 3.85(t, J = 5.2 Hz, 2H), 3.65 (t, J = 6.1 Hz, 2H), 3.38 (t, J = 5.1 Hz, 2H), 3.29– 3.19 (m, 2H), 2.19 (p, J = 5.9 Hz, 2H)。
6-氟-3-{1-[3-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A125”)
米黄色固体; HPLC/MS 1.19 min (A), [M+H]+ 419; 1H NMR (400 MHz, DMSO-d6,TFA-d1) δ 9.31 (s, 1H), 8.86 (s, 1H), 8.18 – 8.10 (m, 2H), 7.75 – 7.64 (m,2H), 7.59 (d, J = 7.6 Hz, 1H), 7.50 (dd, J = 9.0, 4.7 Hz, 1H), 7.37 (td, J =8.8, 2.8 Hz, 1H), 3.89 (bs, 4H), 3.27 (s, 4H)。
7-氯-3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A126”)
白色固体; HPLC/MS 1.27 min (A), [M+H]+ 435; 1H NMR (400 MHz, DMSO-d6) δ12.28 (bs, 1H), 9.25 (s, 1H), 8.85 (s, 1H), 8.08 (d, J = 8.6 Hz, 2H), 7.95(d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 2.0 Hz, 1H), 7.30(dd, J = 8.4, 2.0 Hz, 1H), 3.65 – 3.35 (m, 4H), 2.72 (bs, 4H)。
5,6-二氟-3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A127”)
米黄色固体; HPLC/MS 1.20 min (A), [M+H]+ 437; 1H NMR (400 MHz, DMSO-d6,TFA-d1) δ 9.27 (s, 1H), 8.83 (s, 1H), 8.13 – 8.04 (m, 2H), 7.69 (d, J = 8.2Hz, 2H), 7.51 (q, J = 9.3, 8.9 Hz, 1H), 7.22 (dd, J = 9.4, 3.6 Hz, 1H), 3.73(bs, 4H), 3.20 (bs, 4H)。
6,7-二氟-3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A128”)
盐酸盐: 米黄色固体; UPLC/MS 0.48 min, [M+H]+ 437; 1H NMR (500 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.29 (s, 1H), 8.97 (bs, 2H), 8.85 (s, 1H), 8.23 – 8.02(m, 3H), 7.71 (d, J = 8.5 Hz, 2H), 7.35 (dd, J = 11.4, 7.0 Hz, 1H), 3.71 (bs,4H), 3.16 (bs, 4H)。
6-氟-3-{1-[4-(哌嗪-1-磺酰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A129”)
盐酸盐: 米黄色粉末; UPLC/MS 0.50 min, [M+H]+ 455; 1H NMR (500 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.42 (s, 1H), 9.07 (s, 2H), 8.87 (s, 1H), 8.58 – 8.28(m, 2H), 8.17 – 7.95 (m, 2H), 7.81 (dd, J = 9.2, 2.7 Hz, 1H), 7.56 – 7.37 (m,2H), 3.26 – 3.19 (m, 8H)。
6,7-二氟-3-{1-[4-(2-哌嗪-1-基-乙氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A130”)
浅棕色固体; HPLC/MS 1.20 min (A), [M+H]+ 453。
6-氟-3-{1-[4-(3-哌嗪-1-基-丙氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A131”)
灰白色粉末; HPLC/MS 1.15 min (A), [M+H]+ 449。
6-氟-3-{1-[4-(哌啶-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A132”)
盐酸盐: 米黄色固体; HPLC/MS 1.25 min (A), [M+H]+ 418. 1H NMR (500 MHz,DMSO-d6) δ 12.31 (s, 1H), 9.40 (s, 1H), 8.88 (s, 1H), 8.64 (d, J = 11.5 Hz,1H), 8.45 – 8.33 (m, 1H), 8.25 (m, 4H), 7.83 (dd, J = 9.2, 2.7 Hz, 1H), 7.48(td, J = 8.7, 2.8 Hz, 1H), 7.44 (dd, J = 9.1, 5.0 Hz, 1H), 3.86 (tt, J =11.2, 3.6 Hz, 1H), 3.37 (d, J = 13.0 Hz, 2H), 3.15 – 3.02 (m, 2H), 2.06 –1.96 (m, 2H), 1.79 (dtd, J = 14.5, 11.4, 10.9, 4.0 Hz, 2H)。
6-氟-3-{1-[4-(2-哌啶-4-基-乙氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A133”)
米黄色固体; HPLC/MS 1.31 min (A), [M+H]+ 434。
6,7-二氟-3-{1-[4-(2-哌啶-4-基-乙氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A134”)
灰白色固体; HPLC/MS 1.34 min (A), [M+H]+ 452。
6,7-二氟-3-{1-[4-(3-哌嗪-1-基-丙氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A135”)
灰白色粉末; HPLC/MS 1.19 min (A), [M+H]+ 467。
6,7-二氟-3-{1-[4-(哌啶-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A136”)
盐酸盐; 米黄色固体; UPLC/MS 0.76 min, [M+H]+ 436. 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 9.37 (s, 1H), 8.86 (s, 1H), 8.83 (bs, 1H), 8.55 (bs,1H), 8.24 (s, 4H), 8.10 (dd, J = 11.0, 8.6 Hz, 1H), 7.35 (dd, J = 11.5, 7.1Hz, 1H), 3.86 (ddd, J = 11.2, 7.7, 3.5 Hz, 1H), 3.33 (m, 2H), 3.08 (q, J =11.8 Hz, 2H), 2.01 (d, J = 14.0 Hz, 2H), 1.89 – 1.68 (m, 2H)。
6-甲基-3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A137”)
盐酸盐: 米黄色固体; UPLC/MS 0.72 min, [M+H]+ 415. 1H NMR (500 MHz, DMSO-d6) δ 12.14 (s, 1H), 9.28 (s, 1H), 9.14 (bs, 2H), 8.77 (s, 1H), 8.29 – 8.00(m, 2H), 7.75 – 7.70 (m, 2H), 7.69 (bs, 1H), 7.41 (dd, J = 8.4, 1.9 Hz, 1H),7.33 (d, J = 8.3 Hz, 1H), 3.74 (bs, 4H), 3.20 (bs, 4H), 2.40 (s, 3H)。
5,7-二氟-3-{1-[1-(2-氧代-2-哌嗪-1-基-乙基)-1H-吲哚-5-基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A138”)
盐酸盐: 米黄色固体; UPLC/MS 0.92 min, [M+H]+ 490。1H NMR (400 MHz, DMSO-d6)δ 12.33 (s, 1H), 9.29 (bs, 2H), 9.11 (s, 1H), 8.84 (s, 1H), 8.12 (d, J = 2.1Hz, 1H), 8.09 (dd, J = 11.1, 8.7 Hz, 1H), 7.69 (dd, J = 8.8, 2.1 Hz, 1H),7.62 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.35 (dd, J = 11.5, 7.1Hz, 1H), 5.34 (s, 2H), 3.84 (bs, 2H), 3.71 (bs, 2H), 3.26 (bs, 2H), 3.12 (bs,2H)。
6,7-二氟-3-{1-[1-(2-氧代-2-哌嗪-1-基-乙基)-1H-吲哚-5-基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A139”)
盐酸盐: 浅黄色固体; UPLC/MS 0.93 min, [M+H]+ 490。
6,7-二氟-3-{1-[4-(2-氧代-2-哌嗪-1-基-乙氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A140”)
盐酸盐: 米黄色固体; UPLC/MS 0.87 min, [M+H]+ 467。1H NMR (400 MHz, DMSO-d6)δ 12.32 (s, 1H), 9.15 (bs, 2H), 9.10 (s, 1H), 8.82 (s, 1H), 8.08 (dd, J =11.0, 8.6 Hz, 1H), 7.93 – 7.83 (m, 2H), 7.34 (dd, J = 11.5, 7.1 Hz, 1H), 7.24– 7.11 (m, 2H), 5.01 (s, 2H), 3.71 (bs, 4H), 3.20 (bs, 2H), 3.11 (bs, 2H)。
6-氟-3-{1-[4-(2-氧代-2-哌嗪-1-基-乙氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A141”)
盐酸盐: 米黄色固体; UPLC/MS 0.84 min, [M+H]+ 449。
3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-7-三氟甲基-1H-喹啉-2-酮 (“A142”)
盐酸盐: 米黄色固体; UPLC/MS 0.92 min, [M+H]+ 469。
3-{1-[4-(4-氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 (“A143”)
盐酸盐: 浅米黄色固体; UPLC/MS 0.85 min, [M+H]+ 451。
3-{1-[4-(4-氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A144”)
盐酸盐: 米黄色固体; UPLC/MS 0.81 min, [M+H]+ 433。
6,7-二氟-3-{1-[4-(2-氧代-哌嗪-1-基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A145”)
盐酸盐: 浅棕色固体; HPLC/MS 1.20 min (A), [M+H]+ 423. 1H NMR (400 MHz,DMSO-d6) δ 12.34 (s, 1H), 9.72 (s, 2H), 9.23 (s, 1H), 8.84 (s, 1H), 8.13 –8.03 (m, 3H), 7.64 – 7.55 (m, 2H), 7.34 (dd, J = 11.5, 7.1 Hz, 1H), 3.96 (bs,2H), 3.91 (s, 2H), 3.57 (bs, 2H)。
6,7-二氟-3-{1-[1-(2-氧代-2-哌嗪-1-基-乙基)-1H-吲唑-5-基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A146”)
三氟乙酸盐: 棕色固体; UPLC/MS 0.48 min, [M+H]+ 491. 1H NMR (400 MHz,DMSO-d6) δ 12.33 (s, 1H), 9.21 (s, 1H), 8.85 (s, 1H), 8.76 (s, 2H), 8.39 (d,J = 2.0 Hz, 1H), 8.24 (d, J = 0.9 Hz, 1H), 8.09 (dd, J = 11.0, 8.6 Hz, 1H),8.02 (dd, J = 9.0, 2.1 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.33 (dd, J = 11.4,7.1 Hz, 1H), 5.61 (s, 2H), 3.80 (bs, 2H), 3.65 (bs, 2H), 3.26 (bs, 2H), 3.12(bs, 2H)。
6-氟-7-甲氧基-3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A147”)
浅米黄色固体; HPLC/MS 1.20 min (A), [M+H]+ 449. 1H NMR (400 MHz, DMSO-d6)δ 12.18 (s, 1H), 9.24 (s, 1H), 9.09 (s, 2H), 8.77 (s, 1H), 8.12 (d, J = 8.6Hz, 2H), 7.83 (d, J = 11.6 Hz, 1H), 7.77 – 7.66 (m, 2H), 7.08 (d, J = 7.6 Hz,1H), 3.93 (s, 3H), 3.74 (bs, 4H), 3.20 (b, 4H)。
6-氯-7-氟-3-{1-[4-(哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A148”)
盐酸盐: 米黄色固体; UPLC/MS 0.49 min, [M+H]+ 453. 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.28 (s, 1H), 9.21 (bs, 2H), 8.85 (s, 1H), 8.27 (d, J =8.0 Hz, 1H), 8.13 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.6 Hz, 2H), 7.33 (d, J =10.3 Hz, 1H), 3.36 (bs, 4H), 3.19 (bs, 4H)。
实施例10b
“A118”的合成
向4-{4-[4-(7-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰基}-哌嗪-1-甲酸叔丁酯(83.0 mg, 0.16 mmol)于甲酸(0.9 ml)中的溶液中添加甲醛(37%水溶液, 36.5 µl, 0.49 mmol),并将反应混合物在80℃下搅拌2小时。将反应混合物在减压下浓缩并用饱和NaHCO3溶液处理。将所得沉淀滤出,用水洗涤并在真空下干燥。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,以得到作为灰白色固体的7-氟-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A118”);HPLC/MS 1.19 min (A), [M+H]+ 433。
1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.23 (s, 1H), 8.85 (s, 1H),8.08 (d, J = 8.6 Hz, 2H), 7.99 (dd, J = 9.5, 6.1 Hz, 1H), 7.62 (d, J = 8.6Hz, 2H), 7.18 – 7.09 (m, 2H), 3.86 – 3.32 (m, 4H), 2.35 (bs, 4H), 2.21 (s,3H)。
类似地制备以下化合物:
5-氟-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A149”)
米黄色固体; HPLC/MS 1.22 min (A), [M+H]+ 433; 1H NMR (400 MHz, DMSO-d6) δ12.46 (s, 1H), 9.30 (s, 1H), 8.83 (s, 1H), 8.10 (d, J = 8.6 Hz, 2H), 7.64 (d,J = 8.5 Hz, 2H), 7.58 (td, J = 8.2, 6.0 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H),7.17 – 7.08 (m, 1H), 3.75 – 3.30 (m, 4H), 2.35 (bs, 4H), 2.23 (s, 3H)。
8-氟-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A150”)
灰白色固体; HPLC/MS 1.17 min (A), [M+H]+ 433; 1H NMR (500 MHz, DMSO-d6) δ12.24 (s, 1H), 9.28 (s, 1H), 8.88 (d, J = 1.5 Hz, 1H), 8.13 – 8.05 (m, 2H),7.75 (dd, J = 8.0, 1.1 Hz, 1H), 7.66 – 7.59 (m, 2H), 7.46 (ddd, J = 11.1,8.1, 1.2 Hz, 1H), 7.24 (td, J = 8.0, 4.9 Hz, 1H), 3.78 – 3.30 (m, 4H), 2.44 –2.27 (m, 4H), 2.21 (s, 3H)。
6-氯-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A151”)
灰白色固体; HPLC/MS 1.31 min (A), [M+H]+ 449; 1H NMR (400 MHz, DMSO-d6) δ12.32 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 8.07 (d,J = 2.4 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.60 (dd, J = 9.1, 2.7 Hz, 1H),7.42 (d, J = 8.8 Hz, 1H), 3.75 – 3.30 (m, 4H), 2.36 (bs, 4H), 2.23 (s, 3H)。
5,7-二氟-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A152”)
米黄色固体; HPLC/MS 1.25 min (A), [M+H]+ 451; 1H NMR (500 MHz, DMSO-d6) δ12.54 (s, 1H), 9.28 (s, 1H), 8.77 (s, 1H), 8.10 (d, J = 8.6 Hz, 2H), 7.63 (d,J = 8.6 Hz, 2H), 7.24 (td, J = 10.0, 2.4 Hz, 1H), 7.03 (dt, J = 9.8, 1.7 Hz,1H), 3.72 – 3.32 (m, 4H), 2.35 (bs, 4H), 2.22 (s, 3H)。
6-氟-3-{1-[3-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A153”)
灰白色固体; HPLC/MS 1.20 min (A), [M+H]+ 433; 1H NMR (400 MHz, DMSO-d6) δ12.27 (s, 1H), 9.30 (s, 1H), 8.84 (s, 1H), 8.10 (ddd, J = 8.1, 2.3, 1.0 Hz,1H), 8.02 (t, J = 1.8 Hz, 1H), 7.80 (dd, J = 9.2, 2.6 Hz, 1H), 7.68 (t, J =7.9 Hz, 1H), 7.50 (dt, J = 7.6, 1.3 Hz, 1H), 7.49 – 7.39 (m, 2H), 3.75 – 3.30(m, 4H), 2.45 – 2.25 (m, 4H), 2.21 (s, 3H)。
7-氯-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A154”)
白色固体; HPLC/MS 1.27 min (A), [M+H]+ 449; 1H NMR (400 MHz, DMSO-d6) δ12.28 (s, 1H), 9.26 (s, 1H), 8.86 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.96 (d,J = 8.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 2.0 Hz, 1H), 7.30(dd, J = 8.4, 2.0 Hz, 1H), 3.70 – 3.30 (m, 4H), 2.35 (bs, 4H), 2.22 (s, 3H)。
6-氟-3-{1-[4-(4-甲基-[1,4]二氮杂环庚烷-1-基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-[1,8]萘啶-2-酮 (“A155”)
棕色固体; HPLC/MS 1.18 min (A), [M+H]+ 420; 1H NMR (400 MHz, DMSO-d6) δ12.64 (s, 1H), 9.02 (s, 1H), 8.74 (s, 1H), 8.55 (d, J = 2.9 Hz, 1H), 8.22(dd, J = 8.8, 3.0 Hz, 1H), 7.68 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.2 Hz,2H), 3.63 – 3.54 (m, 2H), 3.50 (t, J = 6.2 Hz, 2H), 2.71 – 2.58 (m, 2H), 2.49– 2.45 (m, 2H), 2.27 (s, 3H), 1.92 (p, J = 5.9 Hz, 3H)。
5,6-二氟-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A156”)
白色固体; HPLC/MS 1.21 min (A), [M+H]+ 451; 1H NMR (400 MHz, DMSO-d6) δ12.48 (s, 1H), 9.31 (s, 1H), 8.81 (s, 1H), 8.13 – 8.06 (m, 2H), 7.72 – 7.60(m, 3H), 7.23 (ddd, J = 9.3, 3.9, 1.6 Hz, 1H), 3.64 (bs, 4H), 2.36 (bs, 4H),2.23 (s, 3H)。
6,7-二氟-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A157”)
白色固体; UPLC/MS 0.49 min, [M+H]+ 451; 1H NMR (500 MHz, DMSO-d6) δ 12.34(s, 1H), 9.92 (bs, 1H), 9.29 (s, 1H), 8.85 (s, 1H), 8.17 – 8.12 (m, 2H), 8.09(dd, J = 10.9, 8.6 Hz, 1H), 7.75 – 7.67 (m, 2H), 7.33 (dd, J = 11.4, 7.1 Hz,1H), 4.44 (bs, 2H), 3.7 (bs, 2H), 3.18 (bs, 4H), 2.81 (s, 3H)。
6-氟-3-{1-[4-(4-甲基-哌嗪-1-磺酰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A158”)
米黄色粉末; UPLC/MS 0.50 min, [M+H]+ 469; 1H NMR (400 MHz, DMSO-d6) δ12.31 (s, 1H), 9.39 (s, 1H), 8.87 (s, 1H), 8.51 – 8.15 (m, 2H), 8.14 – 7.90(m, 2H), 7.81 (dd, J = 9.3, 2.7 Hz, 1H), 7.62 – 7.33 (m, 2H), 2.98 (t, J =4.9 Hz, 4H), 2.38 (t, J = 4.9 Hz, 4H), 2.15 (s, 3H)。
6,7-二氟-3-(1-{4-[2-(4-甲基-哌嗪-1-基)-乙氧基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A159”)
棕色固体; HPLC/MS 1.25 min (A), [M+H]+ 467; 1H NMR (500 MHz, DMSO-d6) δ12.30 (s, 1H), 9.09 (s, 1H), 8.78 (s, 1H), 8.03 (dd, J = 11.0, 8.6 Hz, 1H),7.92 – 7.81 (m, 2H), 7.30 (dd, J = 11.5, 7.1 Hz, 1H), 7.21 – 7.08 (m, 2H),4.16 (t, J = 5.8 Hz, 2H), 2.72 (t, J = 5.8 Hz, 2H), 2.50 (m, 4H), 2.32 (m,4H), 2.15 (s, 3H)。
6-氟-3-(1-{4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A160”)
灰白色粉末; HPLC/MS 1.20 min (A), [M+H]+ 463; 1H NMR (500 MHz, DMSO-d6) δ12.26 (s, 1H), 9.10 (s, 1H), 8.81 (s, 1H), 7.91 – 7.84 (m, 2H), 7.78 (dd, J =9.3, 2.6 Hz, 1H), 7.48 – 7.38 (m, 2H), 7.18 – 7.06 (m, 2H), 4.09 (t, J = 6.4Hz, 2H), 2.43 (t, J = 7.1 Hz, 2H), 2.42 – 2.26 (m, 8H), 2.15 (s, 3H), 1.89(p, J = 6.7 Hz, 2H)。
6-氟-3-{1-[4-(1-甲基-哌啶-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A161”)
浅米黄色固体; HPLC/MS 1.24 min (A), [M+H]+ 432。
6,7-二氟-3-(1-{4-[3-(4-甲基-哌嗪-1-基)-丙氧基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A162”)
浅棕色粉末; HPLC/MS 1.23 min (A), [M+H]+ 481. 1H NMR (500 MHz, DMSO-d6) δ12.30 (s, 1H), 9.09 (s, 1H), 8.79 (s, 1H), 8.04 (dd, J = 11.0, 8.6 Hz, 1H),7.87 (d, J = 9.0 Hz, 2H), 7.30 (dd, J = 11.5, 7.1 Hz, 1H), 7.13 (d, J = 9.0Hz, 2H), 4.09 (t, J = 6.4 Hz, 2H), 2.43 (t, J = 7.1 Hz, 2H), 2.45 – 2.24 (m,8H), 2.15 (s, 3H), 1.89 (p, J = 6.7 Hz, 2H)。
6-氟-3-(1-{4-[2-(1-甲基-哌啶-4-基)-乙氧基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A163”)
灰白色固体; HPLC/MS 1.72 min (A), [M+H]+ 448。
6,7-二氟-3-{1-[4-(1-甲基-哌啶-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A164”)
甲酸盐; 棕色固体; UPLC/MS 0.77 min, [M+H]+ 450。
6-氟-3-(1-{4-[2-(4-甲基-哌嗪-1-基)-2-氧代-乙氧基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A165”)
米黄色固体; UPLC/MS 0.84 min, [M+H]+ 463。
6,7-二氟-3-(1-{4-[2-(1-甲基-哌啶-4-基)-乙氧基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A166”)
甲酸盐: 米黄色固体; HPLC/MS 1.35 min (A), [M+H]+ 466。1H NMR (400 MHz,DMSO-d6) δ 12.33 (s, 1H), 9.08 (s, 1H), 8.81 (s, 1H), 8.30 (s, 1H, 甲酸盐),8.07 (dd, J = 11.0, 8.6 Hz, 1H), 7.95 – 7.73 (m, 2H), 7.32 (dd, J = 11.5, 7.1Hz, 1H), 7.20 – 7.03 (m, 2H), 4.09 (t, J = 6.6 Hz, 2H), 2.82 - 2.76 (m, 2H),2.18 (s, 3H), 1.92 (td, J = 11.7, 2.6 Hz, 2H), 1.65 – 1.72 (m, 4H), 1.50 –1.40 (m, 1H), 1.25 (qd, J = 12.1, 3.8 Hz, 2H)。
6,7-二氟-3-(1-{4-[2-(4-甲基-哌嗪-1-基)-2-氧代-乙氧基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A167”)
甲酸盐: 米黄色固体; UPLC/MS 0.86 min, [M+H]+ 481。
6-甲基-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A168”)
灰白色固体; HPLC/MS 1.22 min (A), [M+H]+ 429. 1H NMR (400 MHz, DMSO-d6) δ12.14 (s, 1H), 9.25 (s, 1H), 8.77 (s, 1H), 8.09 (d, J = 8.6 Hz, 2H), 7.69 (s,1H), 7.63 (d, J = 8.6 Hz, 2H), 7.40 (dd, J = 8.4, 1.9 Hz, 1H), 7.32 (d, J =8.4 Hz, 1H), 3.64 (bs, 2H), 3.40 (bs, 2H), 2.39 (s, 3H), 2.36 (bs, 4H), 2.22(s, 3H)。
6,7-二氟-3-(1-{4-[2-(4-甲基-哌嗪-1-基)-2-氧代-乙基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A169”)
米黄色固体; UPLC/MS 0.97 min, [M+H]+ 465. 1H NMR (400 MHz, DMSO-d6) δ12.32 (s, 1H), 9.17 (s, 1H), 8.84 (s, 1H), 8.08 (dd, J = 11.0, 8.5 Hz, 1H),8.00 – 7.87 (m, 2H), 7.57 – 7.41 (m, 2H), 7.33 (dd, J = 11.4, 7.1 Hz, 1H),3.83 (s, 2H), 3.51 (dt, J = 15.5, 5.0 Hz, 4H), 2.27 (t, J = 5.1 Hz, 4H), 2.18(s, 3H)。
3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-7-三氟甲基-1H-喹啉-2-酮 (“A170”)
米黄色固体; UPLC/MS 0.92 min, [M+H]+ 483. 1H NMR (400 MHz, DMSO-d6) δ12.48 (s, 1H), 9.32 (s, 1H), 8.95 (s, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.13 –8.07 (m, 2H), 7.72 (s, 1H), 7.66 – 7.61 (m, 2H), 7.57 (dd, J = 8.3, 1.7 Hz,1H), 3.73 – 3.34 (m, 4H), 2.34 (bs, 4H), 2.23 (s, 3H)。
3-{1-[4-(4-二甲基氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 (“A171”)
米黄色固体; UPLC/MS 0.86 min, [M+H]+ 479。
3-{1-[4-(4-二甲基氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A172”)
米黄色固体; UPLC/MS 0.83 min, [M+H]+ 461。
6,7-二氟-3-(1-{1-[2-(4-甲基-哌嗪-1-基)-2-氧代-乙基]-1H-吲唑-5-基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A173”)
三氟乙酸盐: 棕色固体; UPLC/MS 0.48 min, [M+H]+ 505. 1H NMR (400 MHz,DMSO-d6) δ 12.33 (s, 1H), 9.87 (s, 1H), 9.21 (s, 1H), 8.85 (s, 1H), 8.39 (d,J = 1.9 Hz, 1H), 8.24 (d, J = 0.8 Hz, 1H), 8.09 (dd, J = 11.0, 8.6 Hz, 1H),8.02 (dd, J = 9.0, 2.1 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.33 (dd, J = 11.4,7.1 Hz, 1H), 5.63 (bs, 2H), 4.5 – 4.1 (m, 2H), 3.6 – 2.9 (m, 6H), 2.86 (s,3H)。
6,7-二氟-3-{1-[4-(4-甲基-2-氧代-哌嗪-1-基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A174”)
米黄色固体; HPLC/MS 1.22 min (A), [M+H]+ 437. 1H NMR (400 MHz, DMSO-d6) δ12.30 (s, 1H), 9.21 (s, 1H), 8.83 (s, 1H), 8.08 (dd, J = 11.0, 8.6 Hz, 1H),8.05 – 8.00 (m, 2H), 7.62 – 7.55 (m, 2H), 7.33 (dd, J = 11.5, 7.0 Hz, 1H),3.78 – 3.71 (m, 2H), 3.16 (s, 2H), 2.77 (t, J = 5.4 Hz, 2H), 2.31 (s, 3H)。
6-氟-3-{1-[4-((R)-1-甲基-吡咯烷-3-基氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A367”)
HPLC/MS 1.23 min (A), [M+H]+ 406;
1H NMR (400 MHz, DMSO-d 6) δ 12.24 (s, 1H), 9.10 (s, 1H), 8.82 (s, 1H),7.98 – 7.85 (m, 2H), 7.80 (dd, J = 9.3, 2.6 Hz, 1H), 7.53 – 7.36 (m, 2H),7.17 – 7.02 (m, 2H), 5.05 – 4.93 (m, 1H), 2.81 (dd, J = 10.4, 6.0 Hz, 1H),2.74 – 2.63 (m, 2H), 2.42 – 2.30 (m, 2H), 2.28 (s, 3H), 1.87 – 1.76 (m, 1H)。
6-氯-3-{1-[4-((S)-1-甲基-吡咯烷-3-基氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A368”)
HPLC/MS 1.31 min (A), [M+H]+ 422;
1H NMR (400 MHz, DMSO-d 6) δ 12.30 (s, 1H), 9.10 (s, 1H), 8.81 (s, 1H),8.05 (d, J = 2.3 Hz, 1H), 7.87 (d, J = 8.9 Hz, 2H), 7.59 (dd, J = 8.8, 2.4Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 8.9 Hz, 2H), 5.01 – 4.93 (m,1H), 2.81 (dd, J = 10.5, 6.0 Hz, 1H), 2.76 – 2.63 (m, 2H), 2.43 – 2.29 (m,2H), 2.29 (s, 3H), 1.90 – 1.74 (m, 1H)。
6-氯-3-{1-[4-((R)-1-甲基-吡咯烷-3-基氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A369”)
HPLC/MS 1.30 min (A), [M+H]+ 422;
1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 9.10 (s, 1H), 8.82 (s, 1H),8.16 (s, 1H, 甲酸盐-H), 8.05 (d, J = 2.4 Hz, 1H), 7.87 (d, J = 9.0 Hz, 2H),7.59 (dd, J = 8.8, 2.3 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.15 – 7.04 (m,2H), 5.06 – 4.91 (m, 1H), 2.90 - 2.65 (m, 3H), 2.47 – 2.26 (m, 5H), 1.88 –1.77 (m, 1H)。
6-氟-3-{1-[4-((S)-1-甲基-吡咯烷-3-基氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A370”)
HPLC/MS 1.22 min (A), [M+H]+ 406;
1H NMR (400 MHz, DMSO-d 6) δ 12.24 (s, 1H), 9.11 (s, 1H), 8.82 (s, 1H),8.16 (s, 1H, 甲酸盐-H), 7.92 – 7.85 (m, 2H), 7.80 (dd, J = 9.3, 2.6 Hz, 1H),7.50 – 7.38 (m, 2H), 7.14 – 7.06 (m, 2H), 5.03 – 4.92 (m, 1H), 2.93 – 2.63(m, 3H), 2.45 – 2.23 (m, 5H), 1.88 – 1.77 (m, 1H)。
6-氟-3-{1-[4-(1-甲基-哌啶-4-基甲基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A371”)
UPLC/MS 0.52 min, [M+H]+ 418;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.11 (s, 1H), 8.76 (s, 1H), 7.89 –7.78 (m, 2H), 7.60 (dd, J = 9.1, 2.8 Hz, 1H), 7.41 (dd, J = 9.0, 4.7 Hz, 1H),7.35 (d, J = 8.6 Hz, 2H), 7.29 (td, J = 8.8, 2.9 Hz, 1H), 3.38 (d, J = 12.2Hz, 2H), 2.90 – 3.74 (m, 2H), 2.70 (s, 3H), 2.61 (d, J = 6.6 Hz, 2H), 1.85 –1.73 (m, 3H), 1.41 (q, J = 12.3, 11.9 Hz, 2H)。
6,7-二氟-3-{1-[4-((S)-1-甲基-吡咯烷-3-基氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A372”)
UPLC/MS 0.50 min, [M+H]+ 424;
1H NMR (700 MHz, DMSO-d 6) δ 12.33 (s, 1H), 10.25 (s, 1H, NH+), 9.13 (s,1H), 8.82 (s, 1H), 8.08 (dd, J = 10.8, 8.5 Hz, 1H), 7.98 – 7.90 (m, 2H), 7.33(dd, J = 11.3, 7.0 Hz, 1H), 7.25 – 7.12 (m, 2H), 5.28 (bs, 1H), 4.2 – 3.1 (m,4H), 2.93 (s, 3H), 2.8 – 2.0 (m, 2H)。
6,7-二氟-3-{1-[4-((R)-1-甲基-吡咯烷-3-基氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A373”)
UPLC/MS 0.50 min, [M+H]+ 424;
1H NMR (700 MHz, DMSO-d 6) δ 12.33 (s, 1H), 10.25 (s, 1H, NH+), 9.13 (s,1H), 8.82 (s, 1H), 8.08 (dd, J = 10.8, 8.5 Hz, 1H), 7.98 – 7.90 (m, 2H), 7.33(dd, J = 11.3, 7.0 Hz, 1H), 7.25 – 7.12 (m, 2H), 5.28 (bs, 1H), 4.2 – 3.1 (m,4H), 2.93 (s, 3H), 2.8 – 2.0 (m, 2H)。
6-氯-3-{1-[4-(1-甲基-哌啶-4-基甲基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A374”)
UPLC/MS 0.55 min, [M+H]+ 434;
1H NMR (400 MHz, DMSO-d 6) δ 12.32 (s, 1H), 9.18 (s, 1H), 8.83 (s, 1H),8.06 (d, J = 2.4 Hz, 1H), 8.03 – 7.89 (m, 2H), 7.59 (dd, J = 8.8, 2.4 Hz,1H), 7.47 – 7.39 (m, 3H), 3.44 – 3.26 (m, 2H), 2.96 – 2.81 (m, 2H), 2.74 (s,3H), 2.71 – 2.61 (m, 2H), 1.87 – 1.73 (m, 3H), 1.49 – 1.30 (m, 2H)。
6-氟-3-{1-[4-(1-甲基-哌啶-4-基氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A375”)
HPLC/MS 1.28 min (A), [M+H]+ 420;
1H NMR (400 MHz, DMSO-d 6) δ 12.24 (s, 1H), 9.10 (s, 1H), 8.82 (s, 1H),7.93 – 7.83 (m, 2H), 7.79 (dd, J = 9.2, 2.6 Hz, 1H), 7.51 – 7.38 (m, 2H),7.16 (d, J = 9.0 Hz, 1H), 4.48 (tt, J = 8.2, 4.0 Hz, 1H), 2.67 – 2.58 (m,2H), 2.31 – 2.14 (m, 5H), 2.04 – 1.92 (m, 2H), 1.74 – 1.62 (m, 2H)。
6-氯-3-{1-[4-(1-甲基-哌啶-4-基氧基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A376”)
HPLC/MS 1.36 min (A), [M+H]+ 436;
1H NMR (700 MHz, DMSO-d 6) δ 12.32 (s, 1H), 9.10 (s, 1H), 8.81 (s, 1H),8.05 (d, J = 2.4 Hz, 1H), 7.91 – 7.74 (m, 2H), 7.58 (dd, J = 8.8, 2.4 Hz,1H), 7.40 (d, J = 8.7 Hz, 1H), 7.22 – 7.00 (m, 2H), 4.48 (tt, J = 8.3, 3.9Hz, 1H), 2.71 – 2.58 (m, 2H), 2.22 – 2.17 (m, 5H), 2.00 – 1.94 (m, 2H), 1.71– 1.64 (m, 2H)。
实施例11
6-氟-3-(1-{4-[4-(2-甲氧基-乙基)-哌嗪-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-[1,8]萘啶-2-酮 (“A175”)
米黄色固体; HPLC/MS 1.12 min (A), [M+H]+ 478; 1H NMR (400 MHz, DMSO-d6) δ12.72 (s, 1H), 9.29 (s, 1H), 8.86 (s, 1H), 8.61 (d, J = 2.9 Hz, 1H), 8.35(dd, J = 8.7, 3.0 Hz, 1H), 8.09 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.6 Hz,2H), 3.62 (bs, 2H), 3.45 (t, J = 5.7 Hz, 2H), 3.36 (bs, 2H), 3.24 (s, 3H),2.55 – 2.40 (m, 6H)。
实施例12
6-氟-3-(1-{4-[2-(4-甲基-哌嗪-1-基)-乙氧基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A176”)
将6-氟-3-[1-(4-甲氧基-苯基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮(211 mg,0.63 mmol, 类似于实施例1制备)于二氯甲烷(6 ml)中的悬浮液冷却至-78℃,并添加三溴化硼(9.38 ml在二氯甲烷中的1 M溶液, 9.38 mmol)。使混合物达到室温并搅拌18小时。向反应混合物中添加饱和NaHCO3水溶液。将已形成的不溶性固体滤出,用二氯甲烷和水洗涤并在真空下干燥,以得到作为灰色固体的6-氟-3-[1-(4-羟基-苯基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮;UPLC/MS 0.68 min, [M+H]+ 323。
向6-氟-3-[1-(4-羟基-苯基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮(203 mg,0.63 mmol)于THF (2 ml)中的悬浮液中依次添加三苯基膦(198 mg, 0.76 mmol)、2-(4-甲基-哌嗪-1-基)-乙醇(109 mg, 0.76 mmol)和偶氮二甲酸二异丙酯(148 µl, 0.76 mmol)。将反应混合物在室温下搅拌18小时。添加三苯基膦(198 mg, 0.76 mmol)和偶氮二甲酸二异丙酯(148 µl, 0.76 mmol) 并将反应混合物在室温下搅拌55小时。将反应混合物蒸发并用甲醇处理。将不溶性固体收集并通过制备型HPLC纯化,以得到作为白色固体的6-氟-3-(1-{4-[2-(4-甲基-哌嗪-1-基)-乙氧基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮。UPLC/MS 0.49 min, [M+H]+ 449。
1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 9.11 (s, 1H), 8.82 (s, 1H),7.93 – 7.85 (m, 2H), 7.79 (dd, J = 9.2, 2.6 Hz, 1H), 7.51 – 7.38 (m, 2H),7.20 – 7.10 (m, 2H), 4.16 (t, J = 5.8 Hz, 2H), 2.72 (t, J = 5.8 Hz, 2H), 2.50(bs, 4H), 2.33 (bs, 4H), 2.15 (s, 3H)。
实施例13
3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-2-氧代-1,2-二氢-喹啉-7-甲腈 (“A177”)
向反应小瓶中装入7-溴-3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(250 mg, 0.52 mmol)、N-甲基-吡咯烷酮(2.5 ml)和氰化铜(I)(56.1 mg, 0.63mmol)。将反应小瓶用氮气冲洗,封闭并加热至170°。将反应混合物在封闭的反应小瓶中在该温度下搅拌8小时。使反应混合物达到室温并用水处理。将不溶性固体滤出,用水洗涤并在真空下干燥。将残余物通过制备型HPLC纯化,以得到作为米黄色固体的3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-2-氧代-1,2-二氢-喹啉-7-甲腈。HPLC/MS 1.42min (A), [M+H]+ 427; 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.34 (s, 1H),8.94 (s, 1H), 8.18 – 8.08 (m, 3H), 7.76 – 7.73 (m, 1H), 7.71 – 7.63 (m, 3H),3.74 – 3.34 (m, 6H)。
实施例14
6-氟-3-(1-{1-[2-(4-甲基-哌嗪-1-基)-2-氧代-乙基]-1H-吲哚-5-基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A178”)
米黄色固体; HPLC/MS 1.23 min (A), [M+H]+ 486; 1H NMR (400 MHz, DMSO-d6) δ12.25 (s, 1H), 9.13 (s, 1H), 8.85 (s, 1H), 8.12 (d, J = 2.1 Hz, 1H), 7.81(dd, J = 9.2, 2.4 Hz, 1H), 7.69 (dd, J = 8.7, 2.1 Hz, 1H), 7.58 (d, J = 8.8Hz, 1H), 7.52 – 7.38 (m, 3H), 6.62 (d, J = 3.2 Hz, 1H), 5.29 (bs, 2H), 3.64(bs, 2H), 3.52 (bs, 2H), 2.57 (bs, 2H), 2.45 (bs, 2H), 2.33 (s, 3H)。
实施例15
乙酸 (R)-1-{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰基}-吡咯烷-3-基酯 (“A179”)
向{1-[4-((R)-3-羟基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸(94.9mg, 0.30 mmol)和2-氨基-5-氟苯甲醛(41.7 mg, 0.3 mmol)于乙酸酐(1 ml)中的悬浮液中添加三乙胺(166 µl, 1.2 mmol),并将反应混合物在80℃下搅拌30分钟。使反应混合物达到室温并在真空下浓缩。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,以得到作为灰白色固体的乙酸 (R)-1-{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰基}-吡咯烷-3-基酯;HPLC/MS 1.49 min (A), [M+H]+ 462。
1H NMR (400 MHz, DMSO-d6): 旋转异构体的1:1混合物,峰的选择: δ 12.27 (s,1H), 9.29 (s, 1H), 8.85 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.86 – 7.73 (m,3H), 7.51 – 7.39 (m, 2H), 2.06 (s, 旋转异构体1), 1.99 (s, 旋转异构体2)。
类似地制备乙酸 (S)-1-{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰基}-吡咯烷-3-基酯 (“A180”):
灰白色固体; HPLC/MS 1.49 min (A), [M+H]+ 462。1H NMR (400 MHz, DMSO-d6):旋转异构体的1:1混合物,峰的选择: δ 12.27 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H),8.09 (d, J = 8.4 Hz, 2H), 7.86 – 7.73 (m, 3H), 7.51 – 7.39 (m, 2H), 2.06 (s,旋转异构体1), 1.99 (s, 旋转异构体2)。
实施例16
6-氟-3-{1-[4-((R)-3-羟基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A181”)
向乙酸(R)-1-{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰基}-吡咯烷-3-基酯(94.9 mg, 0.30 mmol)和2-氨基-5-氟苯甲醛(21.9 mg, 0.05mmol)于甲醇(1 ml)中的溶液中添加1 M 氢氧化钠溶液(1 ml)并将反应混合物在室温下搅拌3小时。将反应混合物在真空下浓缩并将残余物用水处理。将所得沉淀滤出,用水洗涤并在真空下干燥,以得到作为灰白色固体的6-氟-3-{1-[4-((R)-3-羟基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮;HPLC/MS 1.34 min (A), [M+H]+ 420。
1H NMR (400 MHz, DMSO-d6): 旋转异构体的1:1混合物,峰的选择: δ 12.26 (s,1H), 9.29 (s, 1H), 8.85 (s, 1H), 8.15 – 8.03 (m, 2H), 7.80 (dd, J = 9.2, 2.6Hz, 1H), 7.75 (m, 2H), 7.52 – 7.37 (m, 2H), 5.02 (d, J = 3 Hz, 旋转异构体1),4.96 (d, J = 3.1 Hz, 旋转异构体2), 4.35 (bs, 旋转异构体1), 4.27 (bs, 旋转异构体2)。
类似地制备以下化合物:
6-氟-3-{1-[4-((S)-3-羟基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A182”)
灰白色固体; HPLC/MS 1.34 min (A), [M+H]+ 420; 1H NMR (400 MHz, DMSO-d6):旋转异构体的1:1混合物,峰的选择: δ 12.26 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H),8.15 – 8.03 (m, 2H), 7.80 (dd, J = 9.2, 2.6 Hz, 1H), 7.75 (m, 2H), 7.52 –7.37 (m, 2H), 5.02 (d, J = 3 Hz, 旋转异构体1), 4.96 (d, J = 3.1 Hz, 旋转异构体2), 4.35 (bs, 旋转异构体1), 4.27 (bs, 旋转异构体2)。
6-氟-3-{1-[4-(4-羟基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A183”)
灰白色固体; HPLC/MS 1.36 min (A), [M+H]+ 434; 1H NMR (500 MHz, DMSO-d6) δ12.34 (s, 1H), 9.34 (s, 1H), 8.91 (s, 1H), 8.21 – 8.00 (m, 2H), 7.86 (dd, J =9.3, 2.8 Hz, 1H), 7.74 – 7.60 (m, 2H), 7.59 – 7.39 (m, 2H), 4.85 (d, J = 3.9Hz, 1H), 4.08 (bs, 1H), 3.83 (tq, J = 8.0, 3.8 Hz, 1H), 3.59 (bs, 1H), 3.29(bs, 2H), 1.84 (m, , 2H), 1.46 (m, 2H)。
6-氟-3-{1-[4-(3-羟基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A184”)
米黄色固体; HPLC/MS 1.40 min (A), [M+H]+ 434。
实施例17
4-甲基-3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A185”)
向{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-乙酸 (94.9 mg, 0.30mmol)和1-(2-氨基-苯基)-乙酮(40.6 mg, 0.3 mmol)于乙酸酐(1 ml)中的悬浮液中添加三乙胺(166 µl, 1.2 mmol),并将反应混合物在100℃下搅拌5小时。使反应混合物达到室温,并添加水。将固体滤出并部分溶解于少量DMSO中。添加甲醇。将固体滤出,用甲醇洗涤并在真空下干燥,以得到作为棕色粉末的4-甲基-3-{1-[4-(吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮;UPLC/MS 0.87 min, [M+H]+ 416。
1H NMR (400 MHz, DMSO-d 6) δ 11.98 (s, 1H), 9.10 (s, 1H), 8.20 – 8.03(m, 2H), 7.91 (dd, J = 8.3, 1.3 Hz, 1H), 7.76 – 7.63 (m, 2H), 7.57 (ddd, J =8.3, 7.1, 1.3 Hz, 1H), 7.38 (dd, J = 8.2, 1.2 Hz, 1H), 7.27 (ddd, J = 8.3,7.1, 1.2 Hz, 1H), 3.70 – 3.35 (m, 8H), 2.65 (s, 3H)。
实施例18
6-氟-3-{1-[4-((R)-2-甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A186”)
向硫酸铜(II)五水合物(449 mg, 1.80 mmol)和(2R)-2-[(2R)-3,4-二羟基-5-氧代-2H-呋喃-2-基]-2-羟基-乙醇钠水合物(389 mg, 1.80 mmol)于叔丁醇(20 ml)和水(20ml)的混合物中的悬浮液中添加3-丁炔酸(1.51 g, 18.0 mmol)和4-叠氮基-苯甲酸甲酯(3.19 g, 18.0 mmol)。将反应混合物在80℃下搅拌3小时。使反应混合物达到室温,并倒入水中。将所得沉淀滤出,用水洗涤并在真空下干燥,以得到作为米黄色固体的4-(4-羧基甲基-[1,2,3]三唑-1-基)-苯甲酸甲酯;UPLC/MS 0.55 min, [M+H]+ 262。
向4-(4-羧基甲基-[1,2,3]三唑-1-基)-苯甲酸甲酯(1.23 g, 4.70 mmol)和2-氨基-5-氟-苯甲醛(654 mg, 4.70 mmol)于乙酸酐(4 ml)中的悬浮液中添加三乙胺(2.61ml, 18.8 mmol),并将反应混合物在80℃下搅拌30分钟。将反应混合物用甲醇小心稀释。将固体滤出,用叔丁基甲基醚洗涤并在真空下干燥,以得到作为米黄色固体的4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酸甲酯;UPLC/MS 0.80 min, [M+H]+ 365。
向4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酸甲酯(1.24 g, 3.30 mmol)于甲醇(30 ml)中的悬浮液中添加2 M 氢氧化钠水溶液(8.25 ml,16.5 mmol),并将反应混合物在80℃下搅拌2小时。使反应混合物达到室温并过滤。将固体残余物用过量的0.5 N盐酸研磨。将固体滤出,用水和乙腈洗涤并在真空下干燥,以得到作为米黄色固体的4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酸;UPLC/MS 0.70 min, [M+H]+ 351。
向4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酸(35.0mg, 0.10 mmol)于1,4-二氧杂环己烷(0.5 ml)和DMF (0.5 ml)的混合物中的悬浮液中添加 (R)-2-甲基吡咯烷对甲苯磺酸盐(30.9 mg, 0.12 mmol)、N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(28.8 mg, 0.15 mmol)、1-羟基苯并三唑水合物(13.5 mg, 0.10mmol)和4-甲基吗啉(16.5 µl, 0.15 mmol)。将所得悬浮液在室温下搅拌5小时。将反应混合物倒入水中。将所得沉淀滤出,用水洗涤并干燥。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,以得到作为白色晶体的6-氟-3-{1-[4-((R)-2-甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮;HPLC/MS 1.59 min (A), [M+H]+418。
1H NMR (500 MHz, DMSO-d6), 旋转异构体的混合物; 主要旋转异构体: δ 12.31(s, 1H), 9.30 (s, 1H), 8.86 (s, 1H), 8.26 – 7.95 (m, 2H), 7.82 (dd, J = 9.2,2.8 Hz, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.47 (td, J = 8.8, 2.8 Hz, 1H), 7.43(dd, J = 9.0, 4.9 Hz, 1H), 4.25 – 4.14 (m, 1H), 3.57 – 3.51 (m, 1H), 3.37 –3.32 (m, 1H), 2.10 (dq, J = 13.4, 6.8 Hz, 1H), 1.99 – 1.84 (m, 1H), 1.79 –1.68 (m, 1H), 1.64 – 1.53 (m, 1H), 1.29 (d, J = 6.2 Hz, 3H)。
类似地制备以下化合物:
N-(2-二乙基氨基-乙基)-4-[4-(6,7-二氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰胺 (“A187”)
HPLC/MS 1.27 min (A), [M+H]+ 467;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.33 (s, 1H), 8.86 (s, 1H), 8.20 (d, J= 8.9 Hz, 2H), 8.15 (d, J = 8.8 Hz, 2H), 7.95 (dd, J = 10.8, 8.5 Hz, 1H),7.37 (dd, J = 11.4, 7.0 Hz, 1H), 3.73 (t, J = 6.3 Hz, 2H), 3.36 (t, J = 6.3Hz, 2H), 3.30 (qd, J = 7.0, 3.8 Hz, 4H), 1.29 (t, J = 7.3 Hz, 6H)。
4-[4-(7-氯-6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-N-(2-二乙基氨基-乙基)-苯甲酰胺 (“A188”)
HPLC/MS 1.36 min (A), [M+H]+ 483;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.28 (s, 1H), 8.81 (s, 1H), 8.14 (d, J= 8.8 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H), 7.87 (d, J = 9.6 Hz, 1H), 7.52 (d, J= 6.5 Hz, 1H), 3.65 (t, J = 6.3 Hz, 2H), 3.29 (t, J = 6.5 Hz, 2H), 3.22 (qd,J = 6.9, 3.5 Hz, 3H), 1.22 (t, J = 7.2 Hz, 6H)。
3-(1-{4-[4-(2-二乙基氨基-乙基)-哌嗪-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-6,7-二氟-1H-喹啉-2-酮 (“A189”)
UPLC/MS 0.48 min, [M+H]+ 534;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.24 (s, 1H), 8.80 (s, 1H), 8.10 (d, J= 8.6 Hz, 2H), 7.90 (dd, J = 10.8, 8.4 Hz, 1H), 7.69 (d, J = 8.6 Hz, 2H),7.31 (dd, J = 11.3, 7.1 Hz, 1H), 4,0 – 3,6 (m, 4H), 3.63 – 3.55 (m, 2H), 3.52(dt, J = 10.0, 3.3 Hz, 2H), 3.5 – 3.35 (m, 4H), 3.20 (q, J = 7.2 Hz, 4H),1.22 (t, J = 7.3 Hz, 6H)。
6-氟-3-{1-[4-(4-甲氧基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A190”)
UPLC/MS 0.70 min, [M+H]+ 448;
1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H),8.13 – 8.01 (m, 2H), 7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.69 – 7.58 (m, 2H),7.47 (dd, J = 9.0, 2.7 Hz, 1H), 7.45 – 7.39 (m, 1H), 4,1 - 3,8 (m, 1H), 3.65– 3.41 (m, 2H), 3.27 (s, 3H), 3,4 – 3,1 (m, 2H), 1.87 (bs, 2H), 1.48 (bs,2H)。
6,7-二氟-3-{1-[4-(4-甲氧基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A191”)
UPLC/MS 0.73 min, [M+H]+ 466;
1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.25 (s, 1H), 8.84 (s, 1H),8.29 – 7.99 (m, 3H), 7.76 – 7.58 (m, 2H), 7.32 (dd, J = 11.4, 7.1 Hz, 1H), 4,1 - 3,8 (m, 1H), 3.65 – 3.41 (m, 2H), 3.27 (s, 3H), 3,4 – 3,1 (m, 2H), 1.87(bs, 2H), 1.48 (bs, 2H)。
6,7-二氟-3-{1-[4-((R)-3-甲氧基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A192”)
HPLC/MS 1.56 min (A), [M+H]+ 466;
1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 9.26 (s, 1H), 8.84 (s, 1H),8.13 – 8.04 (m, 3H), 7.61 (d, J = 8.0 Hz, 2H), 7.32 (dd, J = 11.4, 7.1 Hz,1H), 4.0 – 3-6 (m, 1H), 3.5 – 3.0 (m, 7H), 2.0 – 1.35 (m, 4H)。
6,7-二氟-3-{1-[4-((S)-3-甲氧基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A193”)
HPLC/MS 1.56 min (A), [M+H]+ 466;
1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 9.26 (s, 1H), 8.84 (s, 1H),8.13 – 8.04 (m, 3H), 7.61 (d, J = 8.0 Hz, 2H), 7.32 (dd, J = 11.4, 7.1 Hz,1H), 4.0 – 3.6 (m, 1H), 3.5 – 3.0 (m, 7H), 2.0 – 1.35 (m, 4H)。
6-氟-3-{1-[4-((R)-3-甲氧基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A194”)
HPLC/MS 1.52 min (A), [M+H]+ 448。
1H NMR (500 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H),8.18 – 8.04 (m, 2H), 7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.65 – 7.55 (m, 2H),7.52 – 7.37 (m, 2H), 4.0 – 3.6 (m, 1H), 3.5 – 3.0 (m, 7H), 2.01 – 1.34 (m,4H)。
6-氟-3-{1-[4-((S)-3-甲氧基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A195”)
HPLC/MS 1.52 min (A), [M+H]+ 448;
1H NMR (500 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H),8.18 – 8.04 (m, 2H), 7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.65 – 7.55 (m, 2H),7.52 – 7.37 (m, 2H), 4.0 – 3.6 (m, 1H), 3.5 – 3.0 (m, 7H), 2.01 – 1.34 (m,4H)。
N-(2-二乙基氨基-乙基)-4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰胺 (“A196”)
HPLC/MS 1.23 min (A), [M+H]+ 449;
1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 9.31 (s, 1H), 8.86 (s, 1H),8.55 (t, J = 5.7 Hz, 1H), 8.14 (d, J = 8.8 Hz, 2H), 8.06 (d, J = 8.8 Hz, 2H),7.81 (dd, J = 9.2, 2.6 Hz, 1H), 7.56 – 7.36 (m, 2H), 3.38 – 3.32 (m, 2H),2.61 – 2.50 (m, 6H), 0.98 (t, J = 7.1 Hz, 6H)。
6-氟-3-{1-[4-((S)-2-羟基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A197”)
MS [M+H]+ 434;
1H NMR (400 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.29 (s, 1H), 9.30 (s,1H), 8.86 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.81 (dd, J = 9.2, 2.6 Hz, 1H),7.75 (d, J = 8.1 Hz, 2H), 7.51 – 7.39 (m, 2H), 4.88 – 4.68 (m, 1H), 4.18 (br.s, 0,7H), 3.91 (br. s, 0,3H), 3.71 – 3.54 (m, 2H), 3.54 – 3.43 (m, 1H), 3.37(br. s,0,7H), 3.11 (br. s, 0,3H), 2.04 – 1.84 (m,3H), 1.80 – 1.65 (m, 1H)。
6-氟-3-{1-[4-((R)-2-甲氧基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A198”)
MS [M+H]+ 448:
1H NMR (400 MHz, DMSO-d 6) δ 12.29 (s, 1H), 9.29 (s, 1H), 8.86 (s, 1H),8.09 (d, J = 8.2 Hz, 2H), 7.81 (dd, J = 9.3, 2.7 Hz, 1H), 7.72 (d, J = 8.2Hz, 2H), 7.53 – 7.35 (m, 2H), 4.37 – 4.23 (m, 1H), 3.68 – 3.56 (m, 1H), 3.48(t, J = 8.5 Hz, 2H), 3.33 (s, 3H), 3.11 – 2.97 (m, 1H), 2.09 – 1.96 (m, 1H),1.96 – 1.82 (m, 2H), 1.81 – 1.68 (m, 1H)。
6-氟-3-{1-[4-((R)-3-甲氧基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A199”)
HPLC/MS 1.51 min (A), [M+H]+ 448;
1H NMR (500 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H),8.11 – 8.05 (m, 2H), 7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.78 – 7.70 (m, 2H),7.51 – 7.37 (m, 2H), 3.69 – 3.57 (m, 1H), 3.58 – 3.44 (m, 2H), 3.41 – 3.17(m, 6H), 2.55 – 2.40 (m, 1H), 2.05 – 1.90 (m, 1H), 1.72 – 1.60 (m, 1H)。
6,7-二氟-3-{1-[4-((R)-3-甲氧基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A200”)
HPLC/MS 1.55 min (A), [M+H]+ 466;
1H NMR (500 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.25 (s, 1H), 8.83 (s, 1H),8.10 – 8-04 (m, 3H), 7.77 – 7.72 (m, 2H), 7.32 (dd, J = 11.4, 7.0 Hz, 1H),3.69 – 3.57 (m, 1H), 3.58 – 3.44 (m, 2H), 3.42 – 3.46 (m, 1H), 3.36 – 3.19(m, 5H), 2.55 – 2.40 (m, 1H), 2.05 – 1.90 (m, 1H), 1.72 – 1.60 (m, 1H)。
6,7-二氟-3-{1-[4-((S)-3-甲氧基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A201”)
HPLC/MS 1.55 min (A), [M+H]+ 466;
1H NMR (500 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.25 (s, 1H), 8.83 (s, 1H),8.10 – 8-04 (m, 3H), 7.77 – 7.72 (m, 2H), 7.32 (dd, J = 11.4, 7.0 Hz, 1H),3.69 – 3.57 (m, 1H), 3.58 – 3.44 (m, 2H), 3.42 – 3.46 (m, 1H), 3.36 – 3.19(m, 5H), 2.55 – 2.40 (m, 1H), 2.05 – 1.90 (m, 1H), 1.72 – 1.60 (m, 1H)。
6-氟-3-{1-[4-((S)-3-甲氧基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A202”)
HPLC/MS 1.51 min (A), [M+H]+ 448。
1H NMR (500 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H),8.11 – 8.05 (m, 2H), 7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.78 – 7.70 (m, 2H),7.51 – 7.37 (m, 2H), 3.69 – 3.57 (m, 1H), 3.58 – 3.44 (m, 2H), 3.41 – 3.17(m, 6H), 2.55 – 2.40 (m, 1H), 2.05 – 1.90 (m, 1H), 1.72 – 1.60 (m, 1H)。
3-(1-{4-[3-(2-二乙基氨基-乙氧基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-6-氟-1H-喹啉-2-酮 (“A203”)
MS [M+H]+ 519;
1H NMR (400 MHz, DMSO-d 6) ) 2种旋转异构体的混合物 δ 12.27 (s, 1H), 9.29(s, 1H), 8.85 (s, 1H), 8.09 (d, J = 8.3 Hz, 2H), 7.80 (dd, J = 9.2, 2.6 Hz,1H), 7.75 (d, J = 8.6 Hz, 2H), 7.51 – 7.39 (m, 2H), 4.16 (s, 0,4H), 4.07 (s,0,6H), 3.64 (td, J = 13.1, 12.2, 4.6 Hz, 1H), 3.53 (dt, J = 23.1, 6.6 Hz,2H), 3.44 – 3.37 (m, 3H), 2.57 (t, J = 6.2 Hz, 1H), 2.42 (q, J = 7.1 Hz, 2H),2.05 – 1.91 (m, 2H), 0.96 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H)。
6-氟-3-{1-[4-(2-氧杂-7-氮杂-螺[4.4]壬烷-7-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A204”)
MS [M+H]+ 460;
1H NMR (500 MHz, DMSO-d 6) δ 12.27 (s, 1H), 9.29 (d, J = 3.0 Hz, 1H), 8.85(s, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.84 – 7.72 (m, 3H), 7.51 – 7.38 (m, 2H),3.81 (t, J = 7.1 Hz, 1H), 3.78 – 3.47 (m, 6H), 3.43 (s, 1H), 2.03 – 1.85 (m,3H), 1.82 (t, J = 7.1 Hz, 1H)。
6-氟-3-{1-[4-(2-氧杂-6-氮杂-螺[3.4]辛烷-6-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A205”)
MS [M+H]+ 446;
1H NMR (500 MHz, DMSO-d 6) δ 12.29 (s, 1H), 9.30 (d, J = 4.0 Hz, 1H), 8.86(s, 1H), 8.10 (t, J = 8.7 Hz, 2H), 7.81 (dd, J = 9.2, 2.7 Hz, 1H), 7.76 (dd,J = 8.2, 6.1 Hz, 2H), 7.50 – 7.41 (m, 2H), 4.65 (d, J = 5.9 Hz, 1H), 4.55 –4.44 (m, 3H), 3.74 (d, J = 17.9 Hz, 2H), 3.51 (dt, J = 20.1, 7.0 Hz, 2H),2.26 – 2.12 (m, 2H)。
6-氟-3-{1-[4-(3-羟基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A206”)
MS [M+H]+ 434;
1H NMR (500 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.28 (s, 1H), 9.29 (s,1H), 8.86 (s, 1H), 8.09 (dd, J = 8.6, 3.4 Hz, 2H), 7.81 (dd, J = 9.2, 2.7 Hz,1H), 7.76 (d, J = 8.3 Hz, 2H), 7.50 – 7.41 (m, 2H), 4.72 (t, J = 5.3 Hz, 0,4H), 4.65 (t, J = 5.2 Hz, 0,6H), 3.69 – 3.57 (m, 1H), 3.57 – 3.37 (m, 3H),3.30 – 3.23 (m, 2H), 2.45 – 2.24 (m, 1H), 2.03 – 1.87 (m, 1H), 1.75 – 1.60(m, 1H)。
3-{1-[4-(3-二甲基氨基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A207”)
MS [M+H]+ 447;
1H NMR (500 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.29 (s, 1H), 9.29 (s,1H), 8.86 (s, 1H), 8.09 (d, J = 8.6 Hz, 2H), 7.81 (dd, J = 9.2, 2.6 Hz, 1H),7.77 (t, J = 8.9 Hz, 2H), 7.50 – 7.40 (m, 2H), 3.81 – 3.72 (m, 0,5H), 3.71 –3.63 (m, 0,5H), 3.62 – 3.44 (m, 2H), 3.41 – 3.17 (m, 1H), 2.81 – 2.75 (m, 0,5H), 2.74 – 2.64 (m, 0,5H), 2.22 (s, 3H), 2.11 (s, 3H), 2.09 – 2.00 (m, 1H),1.84 – 1.69 (m, 1H)。
6-氟-3-(1-{4-[3-(4-羟基-哌啶-1-基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A208”)
MS [M+H]+ 503;
1H NMR (500 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.29 (s, 1H), 9.29 (s,1H), 8.86 (s, 1H), 8.08 (d, J = 7.7 Hz, 2H), 7.81 (dd, J = 9.2, 2.6 Hz, 1H),7.79 – 7.72 (m, 2H), 7.51 – 7.40 (m, 2H), 3.84 – 3.39 (m, 5H), 3.32 (s, 1H),2.94 – 2.68 (m, 2H), 2.22 – 1.94 (m, 3H), 1.84 – 1.58 (m, 3H), 1.51 – 1.29(m, 2H)。
6-氟-3-(1-{4-[3-(2-吗啉-4-基-乙氧基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A209”)
UPLC/MS 0.48 min, [M+H]+ 533;
1H NMR (500 MHz, DMSO-d6) δ 12.29 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H),8.13 – 8.08 (m, 2H), 7.81 (dd, J = 9.2, 2.7 Hz, 1H), 7.78 – 7.73 (m, 2H),7.51 – 7.39 (m, 2H), 4.20 – 4.50 (m, 1H), 3.74 – 3.37 (m, 12H), 2.46 – 2.32(m, 4H), 2.05 – 1.95 (m, 2H)。
6-氟-3-(1-{4-[(R)-3-(2-甲氧基-乙氧基甲基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A210”)
UPLC/MS 0.69 min, [M+H]+ 492;
1H NMR (500 MHz, DMSO-d6) δ 12.29 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H),8.11 – 8.07 (m, 2H), 7.81 (dd, J = 9.2, 2.7 Hz, 1H), 7.78 – 7.73 (m, 2H),7.49 – 7.40 (m, 2H), 3.73 – 3.14 (m, 13H), 2.54 – 2.42 (m, 1H), 2.08 – 1.90(m, 1H), 1.73 – 1.62 (m, 1H)。
4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-N-(2-甲氧基-乙基)-N-甲基-苯甲酰胺 (“A211”)
HPLC/MS 1.47 min (A), [M+H]+ 422;
1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H),8.07 (d, J = 8.1 Hz, 2H), 7.80 (dd, J = 9.3, 2.6 Hz, 1H), 7.69 – 7.60 (m,2H), 7.50 – 7.39 (m, 2H), 3.72 – 3.55 (m, 2H), 3.45 (bs, 2H), 3.36 – 3.16 (m,3H), 3.00 (s, 3H)。
4-[4-(6,7-二氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-N-(2-甲氧基-乙基)-N-甲基-苯甲酰胺 (“A212”)
HPLC/MS 1.51 min (A), [M+H]+ 440;
1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.25 (s, 1H), 8.84 (s, 1H),8.14 – 8.01 (m, 3H), 7.67 – 7.59 (m, 2H), 7.32 (dd, J = 11.4, 7.0 Hz, 1H),3.72 – 3.55 (m, 2H), 3.45 (bs, 2H), 3.36 – 3.16 (m, 3H), 3.00 (s, 3H)。
6-氟-3-{1-[4-((R)-3-羟基甲基-吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A213”)
MS [M+H]+ 450;
1H NMR (400 MHz, DMSO-d 6) δ 12.28 (s, 1H), 9.28 (s, 1H), 8.86 (s, 1H),8.09 (d, J = 8.5 Hz, 2H), 7.81 (dd, J = 9.3, 2.7 Hz, 1H), 7.67 (d, J = 8.5Hz, 2H), 7.51 – 7.39 (m, 2H), 4.94 (t, J = 5.5 Hz, 1H), 4.52 – 3.35 (m, 8H),3.30 – 2.94 (m, 1H)。
6-氟-3-{1-[4-(2-羟基甲基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A214”)
MS [M+H]+ 448;
1H NMR (400 MHz, DMSO-d 6) δ 12.26 (s, 1H), 9.26 (s, 1H), 8.84 (s, 1H),8.05 (d, J = 8.5 Hz, 2H), 7.79 (dd, J = 9.2, 2.5 Hz, 1H), 7.60 (d, J = 8.5Hz, 2H), 7.51 – 7.38 (m, 2H), 4.79 (t, J = 5.5 Hz, 1H), 4.34 (s, 1H), 3.81 –3.60 (m, 2H), 3.61 – 3.34 (m, 1H), 3.14 – 2.71 (m, 1H), 1.90 – 1.49 (m, 6H),1.50 – 1.30 (m, 1H)。
6-氟-3-{1-[4-((S)-2-甲氧基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A215”)
MS [M+H]+ 448;
1H NMR (400 MHz, DMSO-d 6) δ 12.28 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H),8.08 (d, J = 8.7 Hz, 2H), 7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.71 (d, J = 8.2Hz, 2H), 7.50 – 7.39 (m, 2H), 4.29 (br. s, 1H), 3.61 (br. s, 1H), 3.53 – 3.42(m, 2H), 3.04 (br. s, 1H), 2.11 – 1.96 (m, 1H), 1.96 – 1.83 (m, 2H), 1.81 –1.64 (m, 1H)。
6-氟-3-{1-[4-((S)-3-羟基甲基-吗啉-4-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A216”)
MS [M+H]+ 450;
1H NMR (400 MHz, DMSO-d 6) δ 12.28 (s, 1H), 9.28 (s, 1H), 8.86 (s, 1H),8.09 (d, J = 8.5 Hz, 2H), 7.81 (dd, J = 9.3, 2.7 Hz, 1H), 7.67 (d, J = 8.5Hz, 2H), 7.51 – 7.39 (m, 2H), 4.94 (t, J = 5.5 Hz, 1H), 4.52 – 3.35 (m, 8H),3.30 – 2.94 (m, 1H)。
3-{1-[4-((2S,5S)-2,5-双-甲氧基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A217”)
UPLC/MS 0.75 min, [M+H]+ 492;
1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H),8.27 – 8.03 (m, 2H), 7.82 (dd, J = 9.2, 2.7 Hz, 1H), 7.71 (d, J = 8.6 Hz,2H), 7.59 – 7.36 (m, 2H), 4.38 – 4.27 (m, 1H), 4.20 – 4.12 (m, 1H), 3.58 –3.51 (m, 1H), 3.40 (t, J = 8.4 Hz, 1H), 3.32 (s, 3H), 3.05 – 2.88 (m, 5H),2.26 – 2.13 (m, 1H), 2.10 – 1.96 m, 1H), 1.90 – 1.75 (m, 2H)。
3-{1-[4-((2R,5R)-2,5-双-甲氧基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A218”)
UPLC/MS 0.74 min, [M+H]+ 492;
1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H),8.27 – 8.03 (m, 2H), 7.82 (dd, J = 9.2, 2.7 Hz, 1H), 7.71 (d, J = 8.6 Hz,2H), 7.59 – 7.36 (m, 2H), 4.38 – 4.27 (m, 1H), 4.20 – 4.12 (m, 1H), 3.58 –3.51 (m, 1H), 3.40 (t, J = 8.4 Hz, 1H), 3.32 (s, 3H), 3.05 – 2.88 (m, 5H),2.26 – 2.13 (m, 1H), 2.10 – 1.96 m, 1H), 1.90 – 1.75 (m, 2H)。
3-{1-[4-((2S,5S)-2,5-双-甲氧基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 (“A219”)
UPLC/MS 0.75 min, [M+H]+ 510;
1H NMR (300 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.28 (s, 1H), 8.86 (s, 1H),8.22 – 7.99 (m, 3H), 7.78 – 7.66 (m, 2H), 7.33 (dd, J = 11.5, 7.1 Hz, 1H),4.38 – 4.27 (m, 1H), 4.20 – 4.12 (m, 1H), 3.58 – 3.51 (m, 1H), 3.40 (t, J =8.4 Hz, 1H), 3.32 (s, 3H), 3.05 – 2.88 (m, 5H), 2.26 – 2.13 (m, 1H), 2.10 –1.96 m, 1H), 1.90 – 1.75 (m, 2H)。
3-{1-[4-((2R,5R)-2,5-双-甲氧基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 (“A220”)
UPLC/MS 0.76 min, [M+H]+ 510;
1H NMR (300 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.28 (s, 1H), 8.86 (s, 1H),8.22 – 7.99 (m, 3H), 7.78 – 7.66 (m, 2H), 7.33 (dd, J = 11.5, 7.1 Hz, 1H),4.38 – 4.27 (m, 1H), 4.20 – 4.12 (m, 1H), 3.58 – 3.51 (m, 1H), 3.40 (t, J =8.4 Hz, 1H), 3.32 (s, 3H), 3.05 – 2.88 (m, 5H), 2.26 – 2.13 (m, 1H), 2.10 –1.96 m, 1H), 1.90 – 1.75 (m, 2H)。
6,7-二氟-3-(1-{4-[3-(2-吗啉-4-基-乙氧基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A221”)
UPLC/MS 0.49 min, [M+H]+ 551;
1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.28 (s, 1H), 8.13 – 8.06 (m,3H), 7.78 – 7.73 (m, 2H), 7.33 (dd, J = 11.4, 7.1 Hz, 1H), 4.23 – 3.93 (m,1H), 3.73 – 3.36 (m, 10H), 2.47 – 2.30 (m, 6H), 2.06 – 1.94 (m, 2H)。
6-氟-7-甲基-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A222”)
6,7-二氟-3-(1-{4-[(R)-3-(2-甲氧基-乙氧基甲基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A223”)
HPLC/MS 1.54 min (A), [M+H]+ 510;
1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 9.27 (s, 1H), 8.85 (s, 1H),8.17 – 8.04 (m, 3H), 7.78 – 7.72 (m, 2H), 7.33 (dd, J = 11.4, 7.1 Hz, 1H),3.73 – 3.37 (m, 9H), 3.36 – 3.18 (m, 5H), 2.56 – 2.41 (m, 1H), 2.06 – 1.90(m, 1H), 1.76 – 1.58 (m, 1H)。
6-氟-3-(1-{4-[3-(2-吡咯烷-1-基-乙氧基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A224”)
UPLC/MS 0.49 min, [M+H]+ 517;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.32 (s, 1H), 8.88 (s, 1H), 8.17 –8.11 (m, 2H), 7.84 – 7.72 (m, 3H), 7.48 (dd, J = 9.0, 4.9 Hz, 1H), 7.43 (td,J = 8.7, 2.8 Hz, 1H), 4.32 – 4.12 (m, 1H), 3.83 – 3.31 (m, 10H), 3.21 – 2.98(m, 3H), 2.21 – 1.76 (m, 5H)。
6,7-二氟-3-(1-{4-[3-(2-吡咯烷-1-基-乙氧基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A225”)
UPLC/MS 0.50 min, [M+H]+ 535;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.30 (s, 1H), 8.87 (s, 1H), 8.17 –8.06 (m, 2H), 8.02 (dd, J = 10.9, 8.5 Hz, 1H), 7.82 – 7.76 m, 2H), 7.37 (dd,J = 11.4, 7.1 Hz, 1H), 4.32 – 4.12 (m, 1H), 3.83 – 3.31 (m, 10H), 3.21 – 2.98(m, 3H), 2.21 – 1.76 (m, 5H)。
(R)-1-{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰基}-吡咯烷-3-甲酸酰胺 (“A226”)
UPLC/MS 0.59 min, [M+H]+ 447。
1H NMR (500 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H),8.11 – 8.06 (m, 2H), 7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.78 – 7.72 (m, 2H),7.53 – 7.34 (m, 3H), 6.99 – 6.91 (m, 1H), 3.77 – 3.45 (m, 4H), 3.05 – 2.91(m, 1H), 2.20 – 1.93 (m, 2H)。
6-氟-3-{1-[4-((2S,4R)-4-羟基-2-羟基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A227”)
MS [M+H]+ 450;
1H NMR (500 MHz, DMSO-d 6) δ 12.29 (s, 1H), 9.31 (s, 1H), 8.87 (s, 1H),8.10 (d, J = 8.5 Hz, 2H), 7.82 (dd, J = 9.2, 2.7 Hz, 1H), 7.76 (d, J = 8.5Hz, 2H), 7.53 – 7.37 (m, 2H), 4.83 (d, J = 3.1 Hz, 1H), 4.78 (t, J = 5.9 Hz,1H), 4.31 (q, J = 6.2, 5.2 Hz, 1H), 4.23 (br. s, 1H), 3.79 – 3.69 (m, 1H),3.67 – 3.52 (m, 2H), 3.26 (d, J = 11.1 Hz, 1H), 2.14 – 2.01 (m, 1H), 1.98 –1.85 (m, 1H)。
6-氟-3-{1-[4-(2-氧杂-6-氮杂-螺[3.5]壬烷-6-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A228”)
MS [M+H]+ 460;
1H NMR (400 MHz, DMSO-d 6) δ 12.27 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H),8.10 (d, J = 8.4 Hz, 2H), 7.80 (dd, J = 9.2, 2.6 Hz, 1H), 7.61 (d, J = 7.4Hz, 2H), 7.50 – 7.37 (m, 2H), 4.49 – 3.98 (m, 4H), 3.88 (br. s, 1H), 3.60(br. s, 2H), 3.33 (br. s, 1H), 1.94 – 1.79 (m, 2H), 1.58 – 1.37 (m, 2H)。
6-氟-3-{1-[4-(2-氧杂-7-氮杂-螺[3.5]壬烷-7-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A229”)
MS [M+H]+ 460;
1H NMR (400 MHz, DMSO-d 6) δ 12.27 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H),8.08 (d, J = 8.6 Hz, 2H), 7.80 (dd, J = 9.3, 2.6 Hz, 1H), 7.60 (d, J = 8.6Hz, 2H), 7.50 – 7.37 (m, 2H), 4.35 (s, 4H), 3.55 (br. s, 2H), 3.32 (br. s,2H), 1.83 (br. s, 4H)。
6-氟-3-{1-[4-(4-氧杂环丁烷-3-基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A230”)
MS [M+H]+ 475;
1H NMR (400 MHz, DMSO-d 6) δ 12.27 (s, 1H), 9.32 – 9.23 (m, 1H), 8.85 (s,1H), 8.09 (d, J = 8.6 Hz, 2H), 7.79 (dd, J = 9.2, 2.6 Hz, 1H), 7.63 (d, J =8.6 Hz, 2H), 7.55 – 7.30 (m, 2H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.1Hz, 2H), 3.66 (br. s, 2H), 3.47 (p, J = 6.3 Hz, 1H), 3.42 (br. s, 2H), 2.32(br. s, 4H)。
3-{1-[4-(2,5-二氧杂-8-氮杂-螺[3.5]壬烷-8-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A231”)
MS [M+H]+ 462;
1H NMR (500 MHz, DMSO-d 6) δ 12.27 (s, 1H), 9.30 (s, 1H), 8.85 (s, 1H),8.12 (d, J = 8.1 Hz, 2H), 7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.67 (d, J = 8.4Hz, 2H), 7.53 – 7.33 (m, 2H), 4.60 – 4.12 (m, 4H), 4.03 – 3.32 (m, 6H)。
4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-N-氧杂环丁烷-3-基-苯甲酰胺 (“A232”)
MS [M+H]+ 406;
1H NMR (500 MHz, DMSO-d 6) δ 12.28 (s, 1H), 9.33 (s, 1H), 9.26 (d, J = 6.4Hz, 1H), 8.86 (s, 1H), 8.17 (d, J = 8.8 Hz, 2H), 8.12 (d, J = 8.8 Hz, 2H),7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.52 – 7.37 (m, 2H), 5.04 (ddt, J = 14.0,7.5, 6.5 Hz, 1H), 4.80 (dd, J = 7.5, 6.4 Hz, 2H), 4.63 (t, J = 6.4 Hz, 2H)。
6,7-二氟-3-(1-{4-[(S)-3-(2-甲氧基-乙氧基甲基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A233”)
HPLC/MS 1.54 min (A), [M+H]+ 510;
1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 9.27 (s, 1H), 8.85 (s, 1H),8.17 – 8.04 (m, 3H), 7.78 – 7.72 (m, 2H), 7.33 (dd, J = 11.4, 7.1 Hz, 1H),3.73 – 3.37 (m, 8H), 3.36 – 3.18 (m, 5H), 2.56 – 2.41 (m, 1H), 2.06 – 1.90(m, 1H), 1.76 – 1.58 (m, 1H)。
6-氟-3-{1-[4-(2-氧杂-5-氮杂-螺[3.4]辛烷-5-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A234”)
MS [M+H]+ 446;
1H NMR (500 MHz, DMSO-d 6) δ 12.28 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H),8.09 (d, J = 8.6 Hz, 2H), 7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.75 (d, J = 8.6Hz, 2H), 7.55 – 7.30 (m, 2H), 5.47 (d, J = 5.1 Hz, 2H), 4.33 (d, J = 5.2 Hz,2H), 3.39 (t, J = 6.5 Hz, 2H), 2.34 (t, J = 6.7 Hz, 2H), 1.71 (p, J = 6.6 Hz,2H)。
6-氟-3-{1-[4-(2-氧杂-6-氮杂-螺[3.3]庚烷-6-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A235”)
MS [M+H]+ 432;
1H NMR (400 MHz, DMSO-d 6) δ 12.28 (s, 1H), 9.30 (s, 1H), 8.85 (s, 1H),8.11 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H), 7.80 (dd, J = 9.2, 2.6Hz, 1H), 7.50 – 7.38 (m, 2H), 4.70 (s, 4H), 4.55 (s, 2H), 4.25 (s, 2H)。
6-氟-3-(1-{4-[(S)-3-(2-甲氧基-乙氧基甲基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A236”)
HPLC/MS 1.49 min (A), [M+H]+ 492;
1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.29 (s, 1H), 8.86 (s, 1H),8.16 – 8.03 (m, 2H), 7.81 (dd, J = 9.3, 2.7 Hz, 1H), 7.78 – 7.72 (m, 2H),7.50 – 7.40 (m, 2H)。3.73 – 3.37 (m, 8H), 3.36 – 3.18 (m, 5H), 2.56 – 2.41 (m,1H), 2.06 – 1.90 (m, 1H), 1.76 – 1.58 (m, 1H)。
3-{1-[4-((3R,4S)-3,4-二甲氧基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A237”)
UPLC/MS 0.65 min, [M+H]+ 464;
1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H),8.13 – 8.05 (m, 2H), 7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.78 – 7.72 (m, 2H),7.51 – 7.39 (m, 2H), 4.03 (q, J = 5.1 Hz, 1H), 3.98 – 3.90 (m, 1H), 3.70-3.61 (m, 2H), 3.53 – 3.41 (m, 2H), 3.38 (s, 3H), 3.28 (s, 3H)。
4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-N,N-双-(2-甲氧基-乙基)-苯甲酰胺 (“A238”)
UPLC/MS 0.70 min, [M+H]+ 466;
1H NMR (500 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H),8.12 – 8.02 (m, 2H), 7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.68 – 7.56 (m, 2H),7.51 – 7.39 (m, 2H), 3.75 – 3.11 (m, 14H)。
3-{1-[4-(3-二乙基氨基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 (“A239”)
UPLC/MS 0.50 min, [M+H]+ 507;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.26 (s, 1H), 8.83 (s, 1H), 8.10 (s,1H, 甲酸盐-H), 8.12 – 8.07 (m, 2H), 8.01 (dd, J = 10.9, 8.5 Hz, 1H), 7.78 –7.72 (m, 2H), 7.33 (dd, J = 11.4, 7.1 Hz, 1H), 3.90 – 3.47 (m, 4H), 3.38 –3.04 (m, 6H), 2.72 – 2.57 (m, 1H), 2.23 – 2.07 (m, 1H), 1.78 – 1.66 (m, 1H),1.28 – 1.11 (m, 6H)。
N-(3-乙酰基-3-氮杂-双环[3.1.0]己-6-基)-4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰胺 (“A240”)
MS [M+H]+ 473;
1H NMR (400 MHz, DMSO-d 6) δ 12.29 (s, 1H), 9.32 (s, 1H), 8.87 (s, 1H),8.72 (d, J = 3.9 Hz, 1H), 8.15 (d, J = 8.7 Hz, 2H), 8.06 (d, J = 8.7 Hz, 2H),7.81 (dd, J = 9.2, 2.7 Hz, 1H), 7.52 – 7.38 (m, 2H), 3.66 (qd, J = 10.2, 4.1Hz, 2H), 3.44 – 3.32 (m, 2H), 2.60 (q, J = 2.8 Hz, 1H), 1.94 (s, 3H), 1.90 –1.80 (m, 1H), 1.10 (t, J = 7.0 Hz, 1H)。
6-氟-3-{1-[4-((2S,4R)-2-羟基甲基-4-甲氧基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A241”)
MS [M+H]+ 464;
1H NMR (400 MHz, DMSO-d 6) δ 12.29 (s, 1H), 9.30 (s, 1H), 8.87 (s, 1H),8.11 (d, J = 8.4 Hz, 2H), 7.81 (dd, J = 9.3, 2.7 Hz, 1H), 7.76 (d, J = 8.3Hz, 2H), 7.51 – 7.40 (m, 2H), 4.81 (t, J = 5.8 Hz, 1H), 4.24 (s, 1H), 3.92(s, 1H), 3.82 – 3.71 (m, 1H), 3.67 – 3.50 (m, 2H), 3.40 (d, J = 11.8 Hz, 1H),3.12 (s, 3H), 2.18 – 2.03 (m, 2H)。
(S)-1-{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰基}-吡咯烷-2-甲酸酰胺 (“A242”)
UPLC/MS 0.60 min, [M+H]+ 447;
旋转异构体的混合物,主要旋转异构体的一些信号:1H NMR (400 MHz, DMSO-d6) δ12.28 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H), 8.11 (d, J = 8.6 Hz, 2H), 7.88 –7.73 (m, 3H), 7.53 – 7.38 (m, 3H), 6.97 (bs, 1H), 4.40 (dd, J = 8.3, 5.2 Hz,1H), 3.75 – 3.56 (m, 2H), 2.26 – 2.16 (m, 1H), 1.95 – 1.75 (m, 3H)。
(S)-1-{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰基}-吡咯烷-3-甲酸酰胺 (“A243”)
UPLC/MS 0.60 min, [M+H]+ 447;
1H NMR (500 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H),8.11 – 8.06 (m, 2H), 7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.78 – 7.72 (m, 2H),7.53 – 7.34 (m, 3H), 6.99 – 6.91 (m, 1H), 3.77 – 3.45 (m, 4H), 3.05 – 2.91(m, 1H), 2.20 – 1.93 (m, 2H)。
6-氟-3-{1-[4-((2R,4R)-2-羟基甲基-4-甲氧基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A244”)
MS [M+H]+ 464;
1H NMR (400 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.28 (s, 1H), 9.29 (s,1H), 8.85 (s, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.80 (dd, J = 9.3, 2.7 Hz, 1H),7.73 (d, J = 7.6 Hz, 2H), 7.51 – 7.37 (m, 2H), 4.83 (s, 0,7H), 4.70 (s, 0,3H), 4.22 (br. s, 0,7H), 4.04 (br. s, 0,3H), 3.91 (br. s, 1H), 3.64 (br. s,2H), 3.48 – 3.36 (m, 1H), 3.22 (s, 3H), 2.26 – 2.11 (m, 1H), 2.10 – 1.95 (m,1H)。
6-氟-3-{1-[4-(2-氧杂-5-氮杂-螺[3.5]壬烷-5-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A245”)
MS [M+H]+ 460;
1H NMR (500 MHz, DMSO-d 6) δ 12.27 (s, 1H), 9.30 (s, 1H), 8.85 (s, 1H),8.12 (d, J = 8.6 Hz, 2H), 7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.74 (d, J = 8.6Hz, 2H), 7.52 – 7.35 (m, 2H), 4.71 (d, J = 6.8 Hz, 2H), 4.38 (d, J = 6.9 Hz,2H), 3.23 (t, J = 5.5 Hz, 2H), 2.06 (t, J = 6.0 Hz, 2H), 1.70 (p, J = 6.0 Hz,2H), 1.26 (p, J = 5.7 Hz, 2H)。
6-氯-3-{1-[4-((S)-2-羟基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A246”)
MS [M+H]+ 450;
1H NMR (400 MHz, DMSO-d 6) δ 12.33 (s, 1H), 9.28 (s, 1H), 8.84 (s, 1H),8.08 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 2.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H),7.58 (dd, J = 8.8, 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 4.79 (t, J = 5.4Hz, 1H), 4.17 (s, 1H), 3.60 (s, 2H), 3.48 (dt, J = 10.2, 6.7 Hz, 1H), 3.36(s, 1H), 2.03 – 1.83 (m, 3H), 1.82 – 1.60 (m, 1H)。
6-氯-3-{1-[4-((2R,4R)-2-羟基甲基-4-甲氧基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A247”)
MS [M+H]+ 480;
1H NMR (400 MHz, DMSO-d 6 ) 2种旋转异构体的混合物 δ 12.33 (s, 1H), 9.28 (s,1H), 8.84 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 2.3 Hz, 1H), 7.73(d, J = 8.1 Hz, 2H), 7.58 (dd, J = 8.8, 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz,1H), 4.81 (br. s, 0,7H), 4.68 (br. s, 0,3H), 4.22 (br. s, 0,7H), 4.05 (br. s,0,3H), 3.90 (br. s, 1H), 3.64 (br. s, 2H), 3.49 – 3.35 (m, 1H), 3.22 (s, 3H),2.24 – 2.12 (m, 1H), 2.11 – 1.94 (m, 1H)。
6-氯-3-{1-[4-((2S,4R)-2-羟基甲基-4-甲氧基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A248”)
MS [M+H]+ 480;
1H NMR (500 MHz, DMSO-d 6) δ 12.33 (s, 1H), 9.29 (s, 1H), 8.84 (s, 1H),8.10 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 2.3 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H),7.58 (dd, J = 8.8, 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 4.80 (s, 1H), 4.24(s, 1H), 3.91 (q, J = 4.2 Hz, 1H), 3.74 (d, J = 11.2 Hz, 1H), 3.61 (dd, J =11.7, 3.7 Hz, 1H), 3.55 (d, J = 11.2 Hz, 1H), 3.40 (d, J = 11.7 Hz, 1H), 3.11(s, 3H), 2.08 (dd, J = 8.2, 4.9 Hz, 2H)。
6-氯-3-(1-{4-[3-(4-羟基-哌啶-1-基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A249”)
MS [M+H]+ 519;
1H NMR (400 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.33 (s, 1H), 9.28 (s,1H), 8.84 (s, 1H), 8.07 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 2.3 Hz, 1H), 7.75(t, J = 9.1 Hz, 2H), 7.58 (dd, J = 8.8, 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz,1H), 4.53 (d, J = 4.0 Hz, 0.5H), 4.50 (d, J = 4.0 Hz, 0.5H), 3.83 – 3.37 (m,4H), 3.37 – 3.18 (m, 1H), 2.94 – 2.51 (m, 3H), 2.21 – 1.94 (m, 3H), 1.82 –1.60 (m, 3H), 1.47 – 1.27 (m, 2H)。
6-氯-3-{1-[4-(4-氧杂环丁烷-3-基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A250”)
MS [M+H]+ 491;
1H NMR (400 MHz, DMSO-d 6) δ 12.32 (s, 1H), 9.27 (s, 1H), 8.84 (s, 1H),8.09 (d, J = 8.6 Hz, 2H), 8.05 (d, J = 2.3 Hz, 1H), 7.63 (d, J = 8.6 Hz, 2H),7.58 (dd, J = 8.8, 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 4.55 (t, J = 6.5Hz, 2H), 4.46 (t, J = 6.1 Hz, 2H), 3.66 (br. s, 2H), 3.54 – 3.33 (m, 3H),2.32 (br. s, 4H)。
6-氟-3-(1-{4-[(S)-3-(2-甲氧基-乙氧基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A251”)
HPLC/MS 1.46 min (A), [M+H]+ 478;
1H NMR (500 MHz, DMSO-d6) 2种旋转异构体的混合物: δ 12.29 (s, 1H), 9.30(s, 1H), 8.86 (s, 1H), 8.15 – 8.05 (m, 2H), 7.81 (dd, J = 9.2, 2.7 Hz, 1H),7.78 – 7.72 (m, 0.5 H), 7.54 – 7.38 (m, 2H), 4.21 – 4.17 (m, 0.5 H), 4.13 –4.08 (m, 0.5H), 3.71 – 3.37 (m, 8H), 3.28 (s, 1.5H), 3.21 (s, 11.5H), 2.06 –1.95 (m, 2H)。
6-氟-3-(1-{4-[(R)-3-(2-甲氧基-乙氧基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A252”)
HPLC/MS 1.46 min (A), [M+H]+ 478;
1H NMR (500 MHz, DMSO-d6) 2种旋转异构体的混合物: δ 12.29 (s, 1H), 9.30(s, 1H), 8.86 (s, 1H), 8.15 – 8.05 (m, 2H), 7.81 (dd, J = 9.2, 2.7 Hz, 1H),7.78 – 7.72 (m, 0.5 H), 7.54 – 7.38 (m, 2H), 4.21 – 4.17 (m, 0.5 H), 4.13 –4.08 (m, 0.5H), 3.71 – 3.37 (m, 8H), 3.28 (s, 1.5H), 3.21 (s, 11.5H), 2.06 –1.95 (m, 2H)。
6-氯-3-{1-[4-((S)-2-甲氧基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A253”)
MS [M+H]+ 464;
1H NMR (400 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.33 (s, 1H), 9.28 (s,1H), 8.84 (s, 1H), 8.08 (d, J = 8.6 Hz, 2H), 8.05 (d, J = 2.3 Hz, 1H), 7.71(d, J = 8.4 Hz, 2H), 7.58 (dd, J = 8.8, 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz,1H), 4.29 (br.s, 0.7H), 4.07 (br. s, 0.3H), 3.73 – 3.55 (m, 1H), 3.54 – 3.42(m, 2H), 3.32 (s, 3H), 3.16 – 2.92 (m, 1H), 2.09 – 1.96 (m, 1H), 1.96 – 1.81(m, 2H), 1.81 – 1.63 (m, 1H)。
6-氯-3-{1-[4-(3-二甲基氨基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A254”)
MS [M+H]+ 463;
1H NMR (400 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.33 (s, 1H), 9.28 (s,1H), 8.84 (s, 1H), 8.08 (d, J = 8.6 Hz, 2H), 8.05 (d, J = 2.3 Hz, 1H), 7.75(t, J = 8.0 Hz, 2H), 7.58 (dd, J = 8.7, 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz,1H), 3.79 – 3.71 (m, 0.5H), 3.70 – 3.61 (m, 0.5H), 3.60 – 3.43 (m, 2H), 3.38– 3.20 (m, 1H), 2.82 – 2.61 (m, 1H), 2.20 (s, 3H), 2.11 (s, 3H), 2.10 – 1.97(m, 1H), 1.84 – 1.67 (m, 1H)。
6-氯-3-{1-[4-(2-羟基甲基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A255”)
MS [M+H]+ 464;
1H NMR (500 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.32 (s, 1H), 9.26 (s,1H), 8.84 (s, 1H), 8.12 – 7.99 (m, 3H), 7.65 – 7.52 (m, 3H), 7.40 (d, J = 8.8Hz, 1H), 4.79 (t, J = 5.5 Hz, 1H), 4.73 – 4.52 (m, 0.3H), 4.52 – 4.15 (m,0.7H), 3.95 – 3.36 (m, 3H), 3.19 – 2.77 (m, 1H),1.96 – 1.29 (m, 6H)。
6-氯-3-{1-[4-(2-氧杂-7-氮杂-螺[3.5]壬烷-7-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A256”)
MS [M+H]+ 476;
1H NMR (500 MHz, DMSO-d 6) δ 12.32 (s, 1H), 9.27 (s, 1H), 8.84 (s, 1H),8.08 (d, J = 8.6 Hz, 2H), 8.05 (d, J = 2.3 Hz, 1H), 7.60 (d, J = 8.5 Hz, 2H),7.58 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 4.35 (br. s, 4H), 3.55(br. s, 2H), 3.27 (br. s, 2H), 1.83 (br. s, 4H)。
6-氯-3-{1-[4-(2-氧杂-6-氮杂-螺[3.4]辛烷-6-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A257”)
MS [M+H]+ 462;
1H NMR (500 MHz, DMSO-d 6) δ 12.33 (s, 1H), 9.28 (d, J = 2.4 Hz, 1H), 8.84(s, 1H), 8.09 (t, J = 7.7 Hz, 2H), 8.05 (d, J = 2.0 Hz, 1H), 7.75 (dd, J =8.4, 4.2 Hz, 2H), 7.58 (dd, J = 8.8, 2.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H),4.64 (d, J = 6.0 Hz, 1H), 4.55 – 4.42 (m, 3H), 3.73 (d, J = 14.1 Hz, 2H),3.50 (dt, J = 14.7, 6.9 Hz, 2H), 2.18 (dt, J = 12.8, 7.0 Hz, 2H)。
6-氯-3-{1-[4-(2-氧杂-6-氮杂-螺[3.3]庚烷-6-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A258”)
MS [M+H]+ 448;
1H NMR (500 MHz, DMSO-d 6) δ 1H NMR (500 MHz, DMSO-d 6) δ 12.33 (s, 1H),9.29 (s, 1H), 8.84 (s, 1H), 8.10 (d, J = 8.7 Hz, 2H), 8.05 (d, J = 2.3 Hz,1H), 7.84 (d, J = 8.7 Hz, 2H), 7.58 (dd, J = 8.7, 2.4 Hz, 1H), 7.40 (d, J =8.8 Hz, 1H), 4.70 (s, 4H), 4.55 (s, 2H), 4.25 (s, 2H)。
6-氯-3-(1-{4-[(S)-3-(2-甲氧基-乙氧基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A259”)
HPLC/MS 1.56 min (A), [M+H]+ 494;
1H NMR (400 MHz, DMSO-d6) 2种旋转异构体的混合物: δ 12.33 (s, 1H), 9.29(s, 1H), 8.85 (s, 1H), 8.09 (d, J = 8.3 Hz, 2H), 8.06 (d, J = 2.4 Hz, 1H),7.76 (d, J = 8.3 Hz, 2H), 7.59 (dd, J = 8.8, 2.3 Hz, 1H), 7.41 (d, J = 8.8Hz, 1H), 4.22 – 4.15 (m, 0.5H), 4.13 – 4.07 (m, 0.5H), 3.74 – 3.35 (m, 8H),3.28 (s, 1.5H), 3.21 (s, 1.5H), 2.12 – 1.88 (m, 2H)。
6-氯-3-(1-{4-[(R)-3-(2-甲氧基-乙氧基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A260”)
HPLC/MS 1.56 min (A), [M+H]+ 494;
1H NMR (400 MHz, DMSO-d6) 2种旋转异构体的混合物: δ 12.33 (s, 1H), 9.29(s, 1H), 8.85 (s, 1H), 8.09 (d, J = 8.3 Hz, 2H), 8.06 (d, J = 2.4 Hz, 1H),7.76 (d, J = 8.3 Hz, 2H), 7.59 (dd, J = 8.8, 2.3 Hz, 1H), 7.41 (d, J = 8.8Hz, 1H), 4.22 – 4.15 (m, 0.5H), 4.13 – 4.07 (m, 0.5H), 3.74 – 3.35 (m, 8H),3.28 (s, 1.5H), 3.21 (s, 1.5H), 2.12 – 1.88 (m, 2H)。
6-氟-3-(1-{4-[(R)-3-(2-甲氧基-乙氧基)-吡咯烷-1-羰基]-苯基}-1H-吡唑-4-基)-1H-喹啉-2-酮 (“A261”)
HPLC/MS 1.46 min (A), [M+H]+ 477;
1H NMR (400 MHz, DMSO-d6) 2种旋转异构体的混合物 δ 12.12 (s, 1H), 9.20 (s,1H), 8.47 (s, 1H), 8.42 (s, 1H), 8.01 – 7.91 (m, 2H), 7.70 (d, J = 8.4 Hz,2H), 7.49 (dt, J = 9.3, 1.7 Hz, 1H), 7.44 – 7.35 (m, 2H), 4.21 – 4.14 (m,0.5H), 4.13 – 4.06 (m, 0.5H), 3.75 – 3.35 (m, 7H), 3.28 (s, 1.5H), 3.21 (s,1.5H), 2.05 – 1.93 (m, 2H)。
(R)-1-{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯甲酰基}-吡咯烷-2-甲酸酰胺 (“A262”)
UPLC/MS 0.62 min, [M+H]+ 447;
旋转异构体的混合物,主要旋转异构体的一些信号: 1H NMR (400 MHz, DMSO-d6) δ12.28 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H), 8.11 (d, J = 8.6 Hz, 2H), 7.88 –7.73 (m, 3H), 7.53 – 7.38 (m, 3H), 6.97 (bs, 1H), 4.40 (dd, J = 8.3, 5.2 Hz,1H), 3.75 – 3.56 (m, 2H), 2.26 – 2.16 (m, 1H), 1.95 – 1.75 (m, 3H)。
3-{1-[4-((3R,4R)-3,4-二甲氧基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A263”)
HPLC/MS 1.49 min (A), [M+H]+ 464;
1H NMR (400 MHz, DMSO-d 6) δ 12.29 (s, 1H), 9.31 (s, 1H), 8.86 (s, 1H),8.13 – 8.06 (m, 2H), 7.81 (dd, J = 9.3, 2.7 Hz, 1H), 7.79 – 7.73 (m, 2H),7.52 – 7.39 (m, 2H), 3.97 – 3.92 (m, 1H), 3.91 – 3.87 (m, 1H), 3.76 – 3.62(m, 2H), 3.56 (d, J = 13.4 Hz, 1H), 3.43 (d, J = 11.7 Hz, 1H), 3.36 (s, 3H),3.26 (s, 3H)。
3-{1-[4-((3S,4S)-3,4-二甲氧基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A264”)
HPLC/MS 1.49 min (A), [M+H]+ 464;
1H NMR (400 MHz, DMSO-d 6) δ 12.29 (s, 1H), 9.31 (s, 1H), 8.86 (s, 1H),8.13 – 8.06 (m, 2H), 7.81 (dd, J = 9.3, 2.7 Hz, 1H), 7.79 – 7.73 (m, 2H),7.52 – 7.39 (m, 2H), 3.97 – 3.92 (m, 1H), 3.91 – 3.87 (m, 1H), 3.76 – 3.62(m, 2H), 3.56 (d, J = 13.4 Hz, 1H), 3.43 (d, J = 11.7 Hz, 1H), 3.36 (s, 3H),3.26 (s, 3H)。
6-氟-3-{1-[4-((S)-3-氟-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A265”)
MS [M+H]+ 422;
1H NMR (500 MHz, DMSO-d 6) δ 12.28 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H),8.11 (d, J = 8.6 Hz, 2H), 7.81 (dd, J = 9.2, 2.4 Hz, 2H), 7.77 (d, J = 8.4Hz, 1H), 7.50 – 7.40 (m, 2H), 5.38 (dd, J = 52.9, 40.3 Hz, 1H), 3.94 – 3.52(m, 4H), 2.30 – 2.02 (m, 2H)。
6-氯-3-{1-[4-((S)-3-氟-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A266”)
MS [M+H]+ 438;
1H NMR (500 MHz, DMSO-d 6) δ 12.34 (s, 1H), 9.30 (s, 1H), 8.85 (s, 1H),8.11 (d, J = 8.6 Hz, 2H), 8.06 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H),7.77 (d, J = 8.3 Hz, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H), 7.42 (d, J = 8.8Hz, 1H), 5.53 – 5.23 (m, 1H), 3.94 – 3.52 (m, 4H), 2.30 – 2.00 (m, 2H)。
3-{1-[4-(3,3-二氟-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A267”)
MS [M+H]+ 440;
1H NMR (500 MHz, DMSO-d 6) δ 12.29 (s, 1H), 9.31 (s, 1H), 8.86 (s, 1H),8.12 (d, J = 8.6 Hz, 2H), 7.84 – 7.76 (m, 3H), 7.50 – 7.40 (m, 2H), 3.96 (t,J = 13.2 Hz, 2H), 3.76 (br. s, 2H), 2.48 (br. s, 2H)。
6-氯-3-{1-[4-(3,3-二氟-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A268”)
MS [M+H]+ 440;
1H NMR (500 MHz, DMSO-d 6) δ 1H NMR (500 MHz, DMSO-d 6) δ 12.34 (s, 1H),9.31 (s, 1H), 8.86 (s, 1H), 8.12 (d, J = 8.6 Hz, 2H), 8.07 (d, J = 2.4 Hz,1H), 7.81 (d, J = 8.2 Hz, 2H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H), 7.42 (d, J =8.8 Hz, 1H), 3.96 (t, J = 13.2 Hz, 2H), 3.76 (br. s, 2H), 2.48 (br.s, 2H)。
6-氟-3-{1-[4-((R)-3-氟-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A269”)
MS [M+H]+ 421;
1H NMR (500 MHz, DMSO-d 6) δ 12.27 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H),8.09 (d, J = 8.6 Hz, 2H), 7.83 – 7.74 (m, 3H), 7.50 – 7.41 (m, 2H), 5.52 –5.20 (m, 1H), 3.91 – 3.58 (m, 4H), 2.29 – 2.02 (m, 2H)。
6-氯-3-{1-[4-((R)-3-氟-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A270”)
MS [M+H]+ 438;
1H NMR (500 MHz, DMSO-d 6) δ 12.34 (s, 1H), 9.30 (s, 1H), 8.85 (s, 1H),8.11 (d, J = 8.6 Hz, 2H), 8.06 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H),7.77 (d, J = 8.3 Hz, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H), 7.42 (d, J = 8.8Hz, 1H), 5.53 – 5.23 (m, 1H), 3.94 – 3.52 (m, 4H), 2.30 – 2.00 (m, 2H)。
6-氯-3-{1-[4-((3R,4R)-3,4-二甲氧基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A271”)
HPLC/MS 1.60 min (A), [M+H]+ 480;
1H NMR (400 MHz, DMSO-d 6) δ 12.33 (s, 1H), 9.30 (s, 1H), 8.85 (s, 1H),8.13 – 8.07 (m, 2H), 8.06 (d, J = 2.4 Hz, 1H), 7.81 – 7.73 (m, 2H), 7.60 (dd,J = 8.8, 2.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 3.94 (bs, 1H), 3.89 (bs, 1H),3.69 (td, J = 14.3, 13.2, 4.5 Hz, 2H), 3.56 (d, J = 13.4 Hz, 1H), 3.43 (d, J= 11.7 Hz, 1H), 3.37 (s, 3H), 3.26 (s, 3H)。
6-氯-3-{1-[4-((3S,4S)-3,4-二甲氧基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A272”)
HPLC/MS 1.59 min (A), [M+H]+ 480;
1H NMR (400 MHz, DMSO-d 6) δ 12.33 (s, 1H), 9.30 (s, 1H), 8.85 (s, 1H),8.13 – 8.07 (m, 2H), 8.06 (d, J = 2.4 Hz, 1H), 7.81 – 7.73 (m, 2H), 7.60 (dd,J = 8.8, 2.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 3.94 (bs, 1H), 3.89 (bs, 1H),3.69 (td, J = 14.3, 13.2, 4.5 Hz, 2H), 3.56 (d, J = 13.4 Hz, 1H), 3.43 (d, J= 11.7 Hz, 1H), 3.37 (s, 3H), 3.26 (s, 3H)。
6-氟-3-{1-[4-(吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮(“A273”)
UPLC/MS 0.72 min, [M+H]+ 404;
1H NMR (400 MHz, DMSO-d 6) δ 12.28 (s, 1H), 9.29 (s, 1H), 8.86 (s, 1H),8.18 – 8.03 (m, 2H), 7.81 (dd, J = 9.3, 2.7 Hz, 1H), 7.79 – 7.68 (m, 2H),7.54 – 7.37 (m, 2H), 3.51 (t, J = 6.7 Hz, 2H), 3.46 (t, J = 6.3 Hz, 2H), 1.95– 1.81 (m, 4H)。
6-氟-3-{1-[4-((R)-4-羟基-异噁唑烷-2-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A274”)
MS [M+H]+ 422;
1H NMR (400 MHz, DMSO-d 6) δ 12.28 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H),8.12 (d, J = 8.7 Hz, 2H), 7.92 (d, J = 8.7 Hz, 2H), 7.80 (dd, J = 9.2, 2.6Hz, 1H), 7.50 – 7.39 (m, 2H), 5.49 (d, J = 4.0 Hz, 1H), 4.71 (dt, J = 6.1,4.1 Hz, 1H), 4.03 – 3.91 (m, 2H), 3.87 (d, J = 1.7 Hz, 1H), 3.66 (dd, J =11.5, 1.6 Hz, 1H)。
6-氯-3-{1-[4-((R)-4-羟基-异噁唑烷-2-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A275”)
MS [M+H]+ 438;
1H NMR (400 MHz, DMSO-d 6) δ δ 12.33 (s, 1H), 9.30 (s, 1H), 8.85 (s, 1H),8.12 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 8.7 Hz, 2H),7.59 (dd, J = 8.8, 2.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 5.49 (d, J = 4.0Hz, 1H), 4.77 – 4.62 (m, 1H), 4.03 – 3.91 (m, 2H), 3.86 (dd, J = 8.6, 1.8 Hz,1H), 3.66 (dd, J = 11.4, 1.6 Hz, 1H)。
6-氟-3-{1-[4-((S)-4-羟基-异噁唑烷-2-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A276”)
MS [M+H]+ 422;
1H NMR (400 MHz, DMSO-d 6) δ 12.28 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H),8.12 (d, J = 8.7 Hz, 2H), 7.92 (d, J = 8.7 Hz, 2H), 7.80 (dd, J = 9.2, 2.6Hz, 1H), 7.50 – 7.39 (m, 2H), 5.49 (d, J = 4.0 Hz, 1H), 4.71 (dt, J = 6.1,4.1 Hz, 1H), 4.03 – 3.91 (m, 2H), 3.87 (d, J = 1.7 Hz, 1H), 3.66 (dd, J =11.5, 1.6 Hz, 1H)。
6-氯-3-{1-[4-((S)-4-羟基-异噁唑烷-2-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A277”)
MS [M+H]+ 438;
1H NMR (400 MHz, DMSO-d 6) δ δ 12.33 (s, 1H), 9.30 (s, 1H), 8.85 (s, 1H),8.12 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 8.7 Hz, 2H),7.59 (dd, J = 8.8, 2.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 5.49 (d, J = 4.0Hz, 1H), 4.77 – 4.62 (m, 1H), 4.03 – 3.91 (m, 2H), 3.86 (dd, J = 8.6, 1.8 Hz,1H), 3.66 (dd, J = 11.4, 1.6 Hz, 1H)。
6-氟-3-{1-[4-((R)-2-吡咯烷-1-基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A278”)
HPLC/MS 1.28 min (A), [M+H]+ 487;
1H NMR (500 MHz, DMSO-d 6) δ 12.22 (s, 1H), 9.22 (s, 1H), 8.79 (s, 1H),8.07 – 7.97 (m, 2H), 7.74 (dd, J = 9.2, 2.7 Hz, 1H), 7.70 – 7.60 (m, 2H),7.49 – 7.30 (m, 2H), 4.34 – 3.88 (m, 1H), 3.61 – 3.28 (m, 3H), 2.78 – 2.02(m, 6H), 2.00 – 1.90 (m, 1H), 1.90 – 1.76 (m, 2H), 1.76- 1.32 (m, 4H)。
6-氟-3-{1-[4-((S)-2-吡咯烷-1-基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A279”)
HPLC/MS 1.29 min (A), [M+H]+ 487;
1H NMR (500 MHz, DMSO-d 6) δ 12.22 (s, 1H), 9.22 (s, 1H), 8.79 (s, 1H),8.07 – 7.97 (m, 2H), 7.74 (dd, J = 9.2, 2.7 Hz, 1H), 7.70 – 7.60 (m, 2H),7.49 – 7.30 (m, 2H), 4.34 – 3.88 (m, 1H), 3.61 – 3.28 (m, 3H), 2.78 – 2.02(m, 6H), 2.00 – 1.90 (m, 1H), 1.90 – 1.76 (m, 2H), 1.76- 1.32 (m, 4H)。
3-{1-[4-(氮杂环丁烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A280”)
UPLC/MS 0.70 min, [M+H]+ 390;
1H NMR (400 MHz, DMSO-d 6) δ 12.26 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H),8.22 – 8.00 (m, 2H), 7.94 – 7.84 (m, 2H), 7.81 (dd, J = 9.3, 2.6 Hz, 1H),7.54 – 7.38 (m, 2H), 4.38 (t, J = 7.4 Hz, 2H), 4.10 (t, J = 7.8 Hz, 2H), 2.38– 2.18 (m, 2H)。
6-氟-3-(1-{4-[2-(4-甲基-哌嗪-1-羰基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A281”)
UPLC/MS 0.49 min, [M+H]+ 530;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.20 (s, 1H), 8.76 (s, 1H), 8.00 (d, J= 8.6 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 7.56 (dd, J = 9.1, 2.8 Hz, 1H), 7.39(dd, J = 9.1, 4.7 Hz, 1H), 7.26 (td, J = 8.8, 2.8 Hz, 1H), 5.06 – 4.70 (m,2H), 4.60 – 4.19 (m, 3H), 3.78 – 2.85 (m, 6H), 2.82 (s, 3H), 2.31 – 2.15 (m,2H), 2.03 – 1.70 (m, 2H)。
6-氟-3-{1-[4-((R)-3-甲磺酰基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A282”)
HPLC/MS 1.41 min (A), [M+H]+ 482;
1H NMR (400 MHz, DMSO-d 6) δ 12.29 (s, 1H), 9.31 (s, 1H), 8.86 (s, 1H),8.12 (d, J = 8.4 Hz, 2H), 7.88 – 7.70 (m, 3H), 7.53 – 7.40 (m, 2H), 4.15 –3.55 (m, 5H), 3.13 – 2.99 (m, 3H), 2.43 – 2.20 (m, 2H)。
6-氟-3-{1-[4-((S)-3-甲磺酰基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A283”)
HPLC/MS 1.40 min (A), [M+H]+ 482;
1H NMR (400 MHz, DMSO-d 6) δ 12.29 (s, 1H), 9.31 (s, 1H), 8.86 (s, 1H),8.12 (d, J = 8.4 Hz, 2H), 7.88 – 7.70 (m, 3H), 7.53 – 7.40 (m, 2H), 4.15 –3.55 (m, 5H), 3.13 – 2.99 (m, 3H), 2.43 – 2.20 (m, 2H)。
6-氟-3-{1-[4-(3-甲磺酰基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A284”)
UPLC/MS 0.65 min, [M+H]+ 496;
1H NMR (700 MHz, DMSO-d 6) 旋转异构体的1:1混合物,选择的峰 δ 12.30 (s, 1H),9.31 (s, 0.5 H), 9.30 (s, 0.5 H), 8.86 (s, 1H), 8.13 – 8.08 (m, 2H), 7.81(dd, J = 9.1, 2.9 Hz, 1H), 7.79 – 7.71 (m, 2H), 7.47 (td, J = 8.8, 2.8 Hz,1H), 7.43 (dd, J = 9.0, 4.8 Hz, 1H), 3.05 (s, 1.5H), 2.98 (s, 1.5H)。
6-氟-3-(1-{4-[2-(1-甲基-1H-吡唑-4-基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A285”)
MS [M+H]+ 484;
1H NMR (500 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.32 (s, 1H), 9.31 (s,0,70H), 9.26 (s, 0,30H), 8.86 (s, 1H), 8.09 (d, J = 8.1 Hz, 1,4H), 7.97 (d, J= 8.1 Hz, 0,60H), 7.81 (d, J = 9.1 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.68(s, 1H), 5.26 – 5.14 (m, 0,70H), 4.99 – 4.87 (m, 0,30H), 3.80 (s, 2H), 3.72(s, 1H), 3.71 – 3.61 (m, 1,40H), 3.46 – 3.38 (m, 0,6H), 2.29 – 2.13 (m, 1H),2.02 – 1.75 (m, 3H)。
6-氟-3-{1-[4-(2-吡啶-3-基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A286”)
MS [M+H]+ 481;
1H NMR (500 MHz, DMSO-d6) 旋转异构体的混合物,主要的信号 δ 12.32 (s, 1H),9.32 (s, 1H), 8.87 (s, 1H), 8.57 (d, J = 91.1 Hz, 2H), 8.12 (d, J = 8.5 Hz,2H), 7.90 – 7.85 (m, 2H), 7.84 – 7.78 (m, 2H), 7.54 – 7.31 (m, 3H), 5.18 (t,J = 6.9 Hz, 1H), 3.98 – 3.89 (m, 1H), 3.62 – 3.54 (m, 1H), 2.49 – 2.39 (m,1H), 2.03 – 1.74 (m, 3H)。
6-氟-3-(1-{4-[2-(4-甲基-哌嗪-1-基甲基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A287”)
MS [M+H]+ 516;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.33 (s, 1H), 8.87 (s, 1H), 8.15 (d, J= 8.6 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.78 (dd, J = 9.3, 2.7 Hz, 1H), 7.50– 7.39 (m, 2H), 4.70 – 4.60 (m, 1H), 4.35 – 3.30 (m, 12H), 2.93 (s, 3H), 2.30– 2.16 (m, 1H), 2.03 – 1.73 (m, 3H)。
6-氟-3-{1-[4-(2-甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A288”)
UPLC/MS 0.76 min, [M+H]+ 418;
1H NMR (500 MHz, DMSO-d 6) 旋转异构体的混合物,主要旋转异构体的信号: δ12.31 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H), 8.26 – 7.95 (m, 2H), 7.82 (dd, J =9.2, 2.8 Hz, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.47 (td, J = 8.8, 2.8 Hz, 1H),7.43 (dd, J = 9.0, 4.9 Hz, 1H), 4.25 – 4.14 (m, 1H), 3.57 – 3.51 (m, 1H),3.37 – 3.32 (m, 1H), 2.10 (dq, J = 13.4, 6.8 Hz, 1H), 1.99 – 1.84 (m, 1H),1.79 – 1.68 (m, 1H), 1.64 – 1.53 (m, 1H), 1.29 (d, J = 6.2 Hz, 3H)。
6-氟-3-{1-[4-(2-甲基-2,6-二氮杂-螺[3.4]辛烷-6-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A289”)
UPLC/MS 0.47 min, [M+H]+ 459;
1H NMR (500 MHz, DMSO-d 6) 旋转异构体的1:1混合物 δ 12.33 (s, 1H), 9.89(bs, 1H, NH+), 9.32 (s, 0.5H), 9.31 (s, 0.5H), 8.86 (s, 1H), 8.20 – 8.04 (m,2H), 7.82 (dd, J = 9.2, 2.8 Hz, 1H), 7.79 – 7.74 (m, 2H), 7.48 (ddd, J = 9.2,6.1, 2.3 Hz, 1H), 7.43 (dd, J = 8.8, 4.6 Hz, 1H), 4.26 – 3.94 (m, 4H), 3.79 –3. 69 (m, 2H), 3.59 – 3.48 (m, 2H), 2.87 (s, 1.5H), 2.78 (s, 1.5H), 2.24 –2.13 (m, 2H)。
6-氯-3-{1-[4-(2-甲基-2,6-二氮杂-螺[3.4]辛烷-6-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A290”)
UPLC/MS 0.50 min, [M+H]+ 475;
1H NMR (500 MHz, DMSO-d6) 旋转异构体的1:1混合物 δ 12.38 (s, 1H), 9.83(bs, 1H, NH+), 9.32 (s, 0.5H), 9.31 (s, 0.5H), 8.86 (s, 1H), 8.17 – 8.09 (m,2H), 8.08 (d, J = 2.3 Hz, 1H), 7.78 – 7.74 (m, 2H), 7.61 (dt, J = 8.8, 1.8Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 4.26 – 3.94 (m, 4H), 3.79 – 3. 69 (m, 2H),3.59 – 3.48 (m, 2H), 2.84 (s, 1.5H), 2.75 (s, 1.5H), 2.24 – 2.13 (m, 2H)。
6-氟-3-{1-[4-((3aR,6aR)-5-甲基-六氢-吡咯并[3,4-b]吡咯-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A291”)
HPLC/MS 1.23 min (A), [M+H]+ 459;
1H NMR (500 MHz, DMSO-d6) 旋转异构体的混合物,主要旋转异构体的信号: δ12.33 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H), 8.18 – 8.02 (m, 2H), 7.82 (dd, J =9.2, 2.8 Hz, 1H), 7.75 – 7.70 (m, 1H), 7.47 (td, J = 8.8, 2.8 Hz, 1H), 7.42(dd, J = 9.0, 4.9 Hz, 1H), 4.56 (ddd, J = 8.1, 5.8, 2.2 Hz, 1H), 3.62 (td, J= 10.3, 6.6 Hz, 1H), 3.46 (ddd, J = 10.5, 8.0, 2.7 Hz, 1H), 2.95 – 2.80 (m,1H), 2.74 (dd, J = 9.9, 2.2 Hz, 1H), 2.57 – 2.51 (m, 2H), 2.47 – 2.36 (m,1H), 2.24 (s, 3H), 2.02 – 1.88 (m, 1H), 1.74 (ddd, J = 12.1, 6.0, 2.8 Hz,1H)。
6-氯-3-{1-[4-((R)-2-甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A292”)
HPLC/MS 1.69 min (A), [M+H]+ 434;
1H NMR (500 MHz, DMSO-d6) 旋转异构体的混合物,主要旋转异构体的信号: δ12.37 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H), 8.10 – 8.07 (m, 2H), 8.07 (d, J =2.4 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H), 7.40(d, J = 8.8 Hz, 1H), 4.18 (h, J = 5.9 Hz, 1H), 3.58 – 3.50 (m, 1H), 3.39 –3.32 (m, 1H), 2.10 (dq, J = 13.3, 6.8 Hz, 1H), 1.85 – 1.85 (m, 1H), 1.78 –1.67 (m, 1H), 1.57 (dq, J = 13.4, 6.8 Hz, 1H), 1.28 (d, J = 6.2 Hz, 2H)。
3-{1-[4-(2,2-二甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A293”)
HPLC/MS 1.68 min (A), [M+H]+ 432;
1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.27 (s, 1H), 8.85 (s, 1H),8.05 (d, J = 8.5 Hz, 2H), 7.80 (dd, J = 9.2, 2.6 Hz, 1H), 7.64 (d, J = 8.3Hz, 2H), 7.53 – 7.37 (m, 2H), 3.40 (t, J = 6.5 Hz, 2H), 1.90 – 1.71 (m, 4H),1.53 (s, 6H)。
6-氟-3-(1-{4-[3-(4-甲基-哌嗪-1-羰基)-吡咯烷-1-羰基]-苯基}-1H-[1,2,3]三唑-4-基)-1H-喹啉-2-酮 (“A294”)
UPLC/MS 0.47 min, [M+H]+ 530;
1H NMR (500 MHz, DMSO-d 6) 旋转异构体的1:1混合物,信号的选择 δ 12.31 (s,1H), 9.32 (s, 1H), 8.84 (s, 1H), 8.15 – 8.04 (m, 2H), 7.85 – 7.67 (m, 3H),7.50 – 7.34 (m, 2H), 2.20 (s, 1.5H), 2.15 (s, 1.5H)。
实施例19
6-氟-3-{1-[4-((R)-2-甲基-吡咯烷-1-羰基)-苯基]-1H-吡唑-4-基}-1H-喹啉-2-酮(“A295”)
向4-(1H-吡唑)-1-基)-苯甲酸甲酯(9.58 g, 47.4 mmol)于乙酸(100 ml)中的溶液中添加N-溴代琥珀酰亚胺(9.00 g, 50.6 mmol)。将反应混合物加热至100℃并在该温度下搅拌2小时。使反应混合物达到室温。将固体滤出,用水洗涤并在真空下干燥,以得到作为白色结晶固体的4-(4-溴-1H-吡唑-1-基)苯甲酸甲酯;UPLC/MS 0.82 min, [M+H]+ 281/283。
1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.17 – 8.06 (m, 2H), 8.03 –7.98 (m, 2H), 7.97 (s, 1H), 3.88 (s, 3H)。
将4-(4-溴-1H-吡唑-1-基)苯甲酸甲酯(5.12 g, 18.2 mmol)、双(频哪醇合)二硼(6.10 g, 24.0 mmol)和干燥乙酸钾(5.36 g, 54.6 mmol)于THF (110 ml)中的悬浮液用氮气冲洗并添加双(三苯基膦)氯化钯(II)(260 mg, 0.37 mmol)。将反应混合物在氮气下加热至65℃,并在该温度下搅拌3天。将反应混合物经硅藻土过滤并用二氯甲烷洗涤。将滤液蒸发并在硅胶柱上用环己烷/乙酸乙酯作为洗脱液进行色谱分离,以得到作为白色固体的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-吡唑-1-基]-苯甲酸甲酯;UPLC/MS 0.86 min, [M+H]+ 329。
1H NMR (300 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.11 - 8.03 (m, 4H), 7.93(s, 1H), 3.88 (s, 3H), 1.30 (s, 12H)。
将3-溴-6-氟-1H-喹啉-2-酮(980 mg, 4.05 mmol)、4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-吡唑-1-基]-苯甲酸甲酯(1.46 g, 4.45 mmol)和645 mg(6.44 mmol)碳酸氢钾于DMF (13 ml)和水(6.5 ml)中的悬浮液用氮气冲洗,并添加双(三苯基膦)氯化钯(II)(60 mg, 0.085 mmol)。将混合物在微波反应器中在120℃下照射1小时。使反应混合物达到室温。将固体滤出,用水和甲醇洗涤并在真空下干燥,以得到作为灰色固体的4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-吡唑-1-基]-苯甲酸甲酯;UPLC/MS0.80 min, [M+H]+ 364。
1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 9.25 (s, 1H), 8.51 (s, 1H),8.44 (s, 1H), 8.14 – 8.10 (m, 2H), 8.09 – 8.04 (m, 2H), 7.54 – 7.47 (m, 1H),7.45 – 7.35 (m, 2H), 3.89 (s, 3H)。
向4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-吡唑-1-基]-苯甲酸甲酯(832 mg,2.29 mmol)于甲醇(18 ml)中的溶液中添加2 M 氢氧化钠水溶液(9.5 ml, 19 mmol),并将反应混合物在80℃下搅拌1小时。使反应混合物达到室温,并用2N HCl酸化。将所得沉淀滤出,用水洗涤并在真空下干燥,以得到作为灰色固体的4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-吡唑-1-基]-苯甲酸;UPLC/MS 0.70 min, [M+H]+ 350。
向4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-吡唑-1-基]-苯甲酸(28.0.0 mg,0.08 mmol)于1,4-二氧杂环己烷(0.4 ml)和DMF (0.4 ml)的混合物中的悬浮液中添加(R)-2-甲基吡咯烷对甲苯磺酸盐(25.5 mg, 0.10 mmol)、N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(23.0 mg, 0.12 mmol)、1-羟基苯并三唑水合物(10.8 mg, 0.08 mmol)和4-甲基吗啉(13.2 µl, 0.12 mmol)。将所得悬浮液在室温下搅拌2小时。将反应混合物倒入水中。将所得沉淀滤出,用水洗涤并干燥。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,以得到作为白色晶体的6-氟-3-{1-[4-((R)-2-甲基-吡咯烷-1-羰基)-苯基]-1H-吡唑-4-基}-1H-喹啉-2-酮;HPLC/MS 1.60 min (A), [M+H]+ 417。
1H NMR (500 MHz, DMSO-d6), 旋转异构体的混合物; 主要旋转异构体: δ 12.15(s, 1H), 9.20 (s, 1H), 8.47 (s, 1H), 8.42 (s, 1H), 8.00 – 7.92 (m, 2H), 7.67(d, J = 8.2 Hz, 2H), 7.49 (dd, J = 9.0, 2.5 Hz, 1H), 7.43 – 7.35 (m, 2H),4.20 - 4.11 (m, 1H), 3.59 – 3.50 (m, 1H), 3.42 – 3.34 (m, 1H), 2.09 (dq, J =12.6, 6.2, 5.7 Hz, 1H), 2.00 – 1.82 (m, 1H), 1.77 – 1.66 (m, 1H), 1.63 – 1.51(m, 1H), 1.27 (d, J = 6.2 Hz, 3H)。
类似地制备以下化合物:
6-氟-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-吡唑-4-基}-1H-喹啉-2-酮(“A296”)
UPLC/MS 0.47 min, [M+H]+ 432;
1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 9.18 (s, 1H), 8.46 (s, 1H),8.41 (s, 1H), 8.01 – 7.90 (m, 2H), 7.61 – 7.52 (m, 2H), 7.52 – 7.46 (m, 1H),7.41 – 7.37 (m, 2H), 3.5 (bs, 4H), 2.36 (bs, 4H), 2.22 (s, 3H)。
6-氟-3-{1-[4-((S)-3-甲氧基-吡咯烷-1-羰基)-苯基]-1H-吡唑-4-基}-1H-喹啉-2-酮 (“A297”)
UPLC/MS 0.69 min, [M+H]+ 433;
1H NMR (400 MHz, DMSO-d6) 2种旋转异构体的混合物 δ 12.12 (s, 1H), 9.19 (s,1H), 8.47 (s, 1H), 8.41 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.78 – 7.62 (m,2H), 7.49 (dt, J = 9.1, 1.7 Hz, 1H), 7.42 – 7.36 (m, 2H), 4.07 – 4.00 (m,0.5H), 3.99 – 3.93 (m, 0.5H), 3.71 – 3.40 (m, 4H), 3.29 (s, 1.5H), 3.19 (s,1.5H), 2.13 – 1.87 (m, 2H)。
6-氟-3-{1-[4-((R)-3-甲氧基-吡咯烷-1-羰基)-苯基]-1H-吡唑-4-基}-1H-喹啉-2-酮 (“A298”)
UPLC/MS 0.69 min, [M+H]+ 433;
1H NMR (400 MHz, DMSO-d6) 2种旋转异构体的混合物 δ 12.12 (s, 1H), 9.19 (s,1H), 8.47 (s, 1H), 8.41 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.78 – 7.62 (m,2H), 7.49 (dt, J = 9.1, 1.7 Hz, 1H), 7.42 – 7.36 (m, 2H), 4.07 – 4.00 (m,0.5H), 3.99 – 3.93 (m, 0.5H), 3.71 – 3.40 (m, 4H), 3.29 (s, 1.5H), 3.19 (s,1.5H), 2.13 – 1.87 (m, 2H)。
6-氟-3-(1-{4-[(S)-3-(2-甲氧基-乙氧基)-吡咯烷-1-羰基]-苯基}-1H-吡唑-4-基)-1H-喹啉-2-酮 (“A299”)
UPLC/MS 0.69 min, [M+H]+ 477;
1H NMR (400 MHz, DMSO-d6) 2种旋转异构体的混合物 δ 12.12 (s, 1H), 9.19 (s,1H), 8.47 (s, 1H), 8.42 (s, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.4Hz, 2H), 7.49 (dt, J = 9.1, 1.7 Hz, 1H), 7.44 – 7.34 (m, 2H), 4.22 – 4.14 (m,0.5H), 4.13 – 4.06 (m, 0.5H), 3.73 – 3.36 (m, 8H), 3.28 (s, 1.5H), 3.21 (s,1.5H), 2.06 – 1.90 (m, 2H)。
3-{1-[4-((3R,4R)-3,4-二甲氧基-吡咯烷-1-羰基)-苯基]-1H-吡唑-4-基}-6-氟-1H-喹啉-2-酮 (“A300”)
HPLC/MS 1.50 min (A), [M+H]+ 463;
1H NMR (700 MHz, DMSO-d 6) δ 12.14 (s, 1H), 9.21 (s, 1H), 8.48 (s, 1H),8.43 (s, 1H), 8.00 – 7.93 (m, 2H), 7.74 – 7.67 (m, 2H), 7.50 (dd, J = 9.0,2.5 Hz, 1H), 7.44 – 7.34 (m, 2H), 3.94 (d, J = 4.7 Hz, 1H), 3.91 – 3.86 (m,1H), 3.72 (dd, J = 11.8, 4.3 Hz, 1H), 3.65 (dd, J = 13.3, 4.9 Hz, 1H), 3.55(d, J = 13.4 Hz, 1H), 3.44 (d, J = 11.7 Hz, 1H), 3.36 (s, 3H), 3.25 (s, 3H)。
6-氟-3-{1-[4-((2S,4R)-2-羟基甲基-4-甲氧基-吡咯烷-1-羰基)-苯基]-1H-吡唑-4-基}-1H-喹啉-2-酮 (“A301”)
MS [M+H]+ 463;
1H NMR (500 MHz, DMSO-d 6) δ 12.11 (s, 1H), 9.19 (s, 1H), 8.46 (s, 1H),8.41 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.49 (dt, J= 9.2, 1.5 Hz, 1H), 7.39 (dd, J = 7.5, 2.0 Hz, 2H), 4.79 (t, J = 5.8 Hz, 1H),4.23 (br. s, 1H), 3.90 (br. s, 1H), 3.78 – 3.67 (m, 1H), 3.61 (dd, J = 11.8,3.6 Hz, 1H), 3.59 – 3.50 (m, 1H), 3.42 (d, J = 11.7 Hz, 1H), 3.17 (d, J = 5.2Hz, 2H), 3.10 (s, 3H) 2.17 – 1.99 (m, 2H)。
6-氟-3-{1-[4-((2R,4R)-2-羟基甲基-4-甲氧基-吡咯烷-1-羰基)-苯基]-1H-吡唑-4-基}-1H-喹啉-2-酮 (“A302”)
MS [M+H]+ 463;
1H NMR (500 MHz, DMSO-d 6) δ 12.11 (s, 1H), 9.19 (s, 1H), 8.46 (s, 1H),8.41 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.49 (dt, J= 9.2, 1.5 Hz, 1H), 7.41 – 7.37 (m, 2H), 4.81 (br. s, 1H), 4.22 (br. s, 1H),3.90 (br. s, 1H), 3.76 – 3.48 (m, 2H), 3.41 (dd, J = 11.3, 5.0 Hz, 1H), 3.22(s, 3H), 3.17 (d, J = 5.2 Hz, 1H), 2.16 (d, J = 8.3 Hz, 1H), 2.02 (s, 1H)。
3-{1-[4-((3S,4S)-3,4-二甲氧基-吡咯烷-1-羰基)-苯基]-1H-吡唑-4-基}-6-氟-1H-喹啉-2-酮 (“A303”)
HPLC/MS 1.50 min (A), [M+H]+ 463;
1H NMR (700 MHz, DMSO-d 6) δ 12.14 (s, 1H), 9.21 (s, 1H), 8.48 (s, 1H),8.43 (s, 1H), 8.00 – 7.93 (m, 2H), 7.74 – 7.67 (m, 2H), 7.50 (dd, J = 9.0,2.5 Hz, 1H), 7.44 – 7.34 (m, 2H), 3.94 (d, J = 4.7 Hz, 1H), 3.91 – 3.86 (m,1H), 3.72 (dd, J = 11.8, 4.3 Hz, 1H), 3.65 (dd, J = 13.3, 4.9 Hz, 1H), 3.55(d, J = 13.4 Hz, 1H), 3.44 (d, J = 11.7 Hz, 1H), 3.36 (s, 3H), 3.25 (s, 3H)。
6,7-二氟-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-吡唑-4-基}-1H-喹啉-2-酮 (“A304”)
HPLC/MS 1.24 min (A), [M+H]+ 450;
1H NMR (500 MHz, DMSO-d 6) δ 12.20 (s, 1H), 9.16 (s, 1H), 8.43 (s, 1H),8.39 (s, 1H), 8.06 – 7.91 (m, 2H), 7.74 (dd, J = 10.8, 8.4 Hz, 1H), 7.60 –7.49 (m, 2H), 7.29 (dd, J = 11.4, 7.1 Hz, 1H), 3.70 – 3.31 (m, 4H), 2.45 –2.25 (m, 4H), 2.21 (s, 3H)。
6-氯-3-{1-[4-(4-甲基-哌嗪-1-羰基)-苯基]-1H-吡唑-4-基}-1H-喹啉-2-酮(“A305”)
UPLC/MS 0.50 min, [M+H]+ 448;
1H NMR (500 MHz, DMSO-d6) δ 12.13 (bs, 1H), 9.18 (s, 1H), 8.45 (s, 1H),8.40 (s, 1H), 7.99 – 7.93 (m, 2H), 7.74 (d, J = 2.4 Hz, 1H), 7.59 – 7.55 (m,2H), 7.53 (dd, J = 8.7, 2.4 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 3.8 – 3.3 (m,4H), 2.45 – 2.25 (m, 4H), 2.21 (s, 3H)。
实施例20
3-{1-[4-((S)-3-氨基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A306”)
MS [M+H]+ 419; HCl盐;
1H NMR (500 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.30 (s, 1H), 9.31 (s,1H), 8.86 (s, 1H), 8.30 (br. s, 2H), 8.18 (br. s, 1H), 8.13 (d, J = 8.6 Hz,2H), 7.88 – 7.70 (m, 3H), 7.54 – 7.39 (m, 2H), 3.97 – 3.65 (m, 3H), 3.66 –3.45 (m, 2H), 2.25 (br. s, 1H), 2.06 (br. s, 1H)。
类似地制备以下化合物:
6,7-二氟-3-{1-[4-((顺)-六氢-吡咯并[3,4-c]吡咯-2-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A307”)
UPLC/MS 0.47 min, [M+H]+ 463;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.29 (s, 1H), 8.86 (s, 1H), 8.23 –8.09 (m, 2H), 7.98 (dd, J = 10.8, 8.5 Hz, 1H), 7.84 – 7.75 (m, 2H), 7.37 (dd,J = 11.3, 7.0 Hz, 1H), 3,85 – 3,05 (m, 10H)。
6-氟-3-{1-[4-((顺)-六氢-吡咯并[3,4-c]吡咯-2-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A308”)
HPLC/MS 1.25 min (A), [M+H]+ 445;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.32 (s, 1H), 8.87 (s, 1H), 8.12 (d, J= 8.6 Hz, 2H), 7.79 (d, J = 8.6 Hz, 2H), 7.72 (dd, J = 9.1, 2.8 Hz, 1H), 7.49(dd, J = 9.0, 4.7 Hz, 1H), 7.40 (td, J = 8.8, 2.8 Hz, 1H), 3.90 – 3.04 (m,10H)。
3-{1-[4-((R)-3-氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 盐酸盐 (“A309”)
UPLC/MS 0.47 min, [M+H]+ 451;
1H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H),8.34 – 8.01 (m, 6H), 7.69 (d, J = 8.5 Hz, 2H), 7.36 (dd, J = 11.4, 7.0 Hz,1H), 4.47 – 3.01 (m, 4H), 2.14 – 2.01 (m, 1H), 1.86 – 1.49 (m, 4H)。
3-{1-[4-((S)-3-氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 盐酸盐 (“A310”)
UPLC/MS 0.47 min, [M+H]+ 451。
1H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H),8.34 – 8.01 (m, 6H), 7.69 (d, J = 8.5 Hz, 2H), 7.36 (dd, J = 11.4, 7.0 Hz,1H), 4.47 – 3.01 (m, 4H), 2.14 – 2.01 (m, 1H), 1.86 – 1.49 (m, 4H)。
6-氟-3-{1-[4-((R)-3-甲基氨基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮盐酸盐 (“A311”)
MS [M+H]+ 433; HCl盐;
1H NMR (500 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.30 (s, 1H), 9.31 (s,1H), 9.27 – 8.91 (m, 2H, NH2 +), 8.86 (s, 1H), 8.13 (d, J = 8.6 Hz, 2H), 7.85 –7.74 (m, 3H), 7.51 – 7.41 (m, 2H), 3.92 – 3.68 (m, 3H), 3.68 – 3.51 (m, 2H),2.65 (s, 1.8H), 2.56 (s, 1.2H), 2.27 (br. s, 1H), 2.17 (br. s, 1H)。
6-氟-3-{1-[4-((S)-3-甲基氨基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 盐酸盐 (“A312”)
MS [M+H]+ 433; HCl盐;
1H NMR (500 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.30 (s, 1H), 9.31 (s,1H), 9.27 – 8.91 (m, 2H, NH2 +), 8.86 (s, 1H), 8.13 (d, J = 8.6 Hz, 2H), 7.85 –7.74 (m, 3H), 7.51 – 7.41 (m, 2H), 3.92 – 3.68 (m, 3H), 3.68 – 3.51 (m, 2H),2.65 (s, 1.8H), 2.56 (s, 1.2H), 2.27 (br. s, 1H), 2.17 (br. s, 1H)。
3-{1-[4-((R)-3-氨基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 盐酸盐 (“A313”)
MS [M+H]+ 419; HCl盐;
1H NMR (500 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.30 (s, 1H), 9.31 (s,1H), 8.86 (s, 1H), 8.30 (br. s, 2H), 8.18 (br. s, 1H), 8.13 (d, J = 8.6 Hz,2H), 7.88 – 7.70 (m, 3H), 7.54 – 7.39 (m, 2H), 3.97 – 3.65 (m, 3H), 3.66 –3.45 (m, 2H), 2.25 (br. s, 1H), 2.06 (br. s, 1H)。
6-氟-3-{1-[4-((R)-3-羟基甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 盐酸盐 (“A314”)
MS [M+H]+ 449; 二盐酸盐;
1H NMR (500 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 1H NMR (500 MHz, DMSO-d 6) δ 12.29 (s, 1H), 9.42 (br. s, 1H), 9.30 (s, 1H), 9.10 (br. s, 1H), 8.85(s, 1H), 8.12 (d, J = 8.6 Hz, 2H), 7.81 (dd, J = 9.2, 2.7 Hz, 1H), 7.72 (d, J= 8.5 Hz, 2H), 7.50 – 7.40 (m, 2H), 5.47 (s, 1H), 4.49 (br. s, 1H), 3.64 (br.s, 2H), 3.57 (s, 2H), 3.47 – 3.33 (m, 2H), 3.22 – 2.95 (m, 2H)。
6-氟-3-{1-[4-((S)-2-羟基甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A315”)
MS [M+H]+ 449;
1H NMR (500 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.30 (s, 1H), 9.28 (s,1H), 8.86 (s, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.81 (dd, J = 9.2, 2.6 Hz, 1H),7.63 (d, J = 8.4 Hz, 2H), 7.50 – 7.40 (m, 2H), 4.91 (br. s, 1H), 4.49 – 4.04(m, 1H), 3.93 – 3.45 (m, 3H), 3.13 – 2.54 (m, 4H), 2.20 – 1.95 (m, 1H)。
6-氟-3-{1-[4-((R)-2-羟基甲基-哌嗪-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A316”)
MS [M+H]+ 449;
1H NMR (500 MHz, DMSO-d 6) 2种旋转异构体的混合物 δ 12.30 (s, 1H), 9.28 (s,1H), 8.86 (s, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.81 (dd, J = 9.2, 2.6 Hz, 1H),7.63 (d, J = 8.4 Hz, 2H), 7.50 – 7.40 (m, 2H), 4.91 (br. s, 1H), 4.49 – 4.04(m, 1H), 3.93 – 3.45 (m, 3H), 3.13 – 2.54 (m, 4H), 2.20 – 1.95 (m, 1H)。
3-{1-[4-(6-氨基-3-氮杂-双环[3.1.0]己烷-3-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A317”)
MS [M+H]+ 431;
1H NMR (400 MHz, DMSO-d 6) δ 12.33 (s, 1H), 9.29 (s, 1H), 8.86 (s, 1H),8.07 (d, J = 8.7 Hz, 2H), 7.81 (dd, J = 9.2, 2.6 Hz, 1H), 7.67 (d, J = 8.7Hz, 2H), 7.51 – 7.39 (m, 2H), 3.89 (d, J = 12.1 Hz, 1H), 3.66 (dd, J = 10.6,4.4 Hz, 1H), 3.45 (dd, J = 12.0, 4.4 Hz, 1H), 3.38 (d, J = 10.7 Hz, 1H), 2.00(t, J = 2.2 Hz, 1H), 1.56 – 1.41 (m, 2H)。
6-氯-3-{1-[4-((S)-2-二甲基氨基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A318”)
HPLC/MS 1.35 min (A), [M+H]+ 477;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.21 (s, 1H), 8.75 (s, 1H), 8.11 –8.01 (m, 2H), 7.84 (d, J = 2.3 Hz, 1H), 7.78 – 7.72 (m, 2H), 7.43 (dd, J =8.8, 2.3 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 4.55 (qd, J = 7.7, 3.4 Hz, 1H),3.56 (dt, J = 10.3, 7.3 Hz, 1H), 3.50 – 3.38 (m, 2H), 3.18 (dd, J = 13.5, 3.5Hz, 1H), 2.98 (s, 3H), 2.84 (s, 3H), 2.16 (dq, J = 13.2, 6.6 Hz, 1H), 1.86(dq, J = 11.3, 5.8 Hz, 1H), 1.80 – 1.61 (m, 2H)。
3-{1-[4-((S)-2-二甲基氨基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A319”)
UPLC/MS 0.50 min, [M+H]+ 461;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.19 (s, 1H), 8.75 (s, 1H), 8.00 (d, J= 8.2 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.55 – 7.48 (m, 1H), 7.39 (dd, J =9.1, 4.7 Hz, 1H), 7.23 (td, J = 8.8, 2.8 Hz, 1H), 4.57 – 4.47 (m, 1H), 3.63 –3.49 (m, 1H), 3.49 – 3.36 (m, 2H), 3.15 (dd, J = 13.5, 3.3 Hz, 1H), 2.97 (s,3H), 2.82 (s, 3H), 2.20 – 2.10 (m, 1H), 1.97 – 1.79 (m, 1H), 1.79 – 1.58 (m,2H)。
3-{1-[4-((R)-2-二甲基氨基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 (“A320”)
UPLC/MS 0.52 min, [M+H]+ 479;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.17 (s, 1H), 8.74 (s, 1H), 8.01 (d, J= 8.6 Hz, 2H), 7.83 – 7.71 (m, 3H), 7.27 (dd, J = 11.4, 7.0 Hz, 1H), 4.58 –4.48 (m, 1H), 3.63 – 3.50 (m, 1H), 3.49 – 3.36 (m, 2H), 3.16 (dd, J = 13.4,3.4 Hz, 1H), 2.20 – 2.10 (m, 1H), 1.92 – 1.80 (m, 1H), 1.80 – 1.57 (m, 2H)。
3-{1-[4-((R)-2-二甲基氨基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A321”)
UPLC/MS 0.50 min, [M+H]+ 461;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.26 (s, 1H), 8.80 (s, 1H), 8.15 –8.07 (m, 2H), 7.84 – 7.76 (m, 2H), 7.64 (dd, J = 9.1, 2.8 Hz, 1H), 7.42 (dd,J = 9.0, 4.7 Hz, 1H), 7.32 (td, J = 8.8, 2.8 Hz, 1H), 4.57 (qd, J = 7.5, 3.7Hz, 1H), 3.58 (dt, J = 10.5, 7.3 Hz, 1H), 3.49 – 3.41 (m, 2H), 3.20 (dd, J =13.4, 3.8 Hz, 1H), 3.00 (s, 3H), 2.86 (s, 3H), 2.21 – 2.12 (m, 1H), 1.95 –1.84 (m, 1H), 1.82 – 1.64 (m, 2H)。
6-氯-3-{1-[4-((R)-2-二甲基氨基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A322”)
UPLC/MS 0.53 min, [M+H]+ 477;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.21 (s, 1H), 8.75 (s, 1H), 8.11 –8.01 (m, 2H), 7.84 (d, J = 2.3 Hz, 1H), 7.78 – 7.72 (m, 2H), 7.43 (dd, J =8.8, 2.3 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 4.55 (qd, J = 7.7, 3.4 Hz, 1H),3.56 (dt, J = 10.3, 7.3 Hz, 1H), 3.50 – 3.38 (m, 2H), 3.18 (dd, J = 13.5, 3.5Hz, 1H), 2.98 (s, 3H), 2.84 (s, 3H), 2.16 (dq, J = 13.2, 6.6 Hz, 1H), 1.86(dq, J = 11.3, 5.8 Hz, 1H), 1.80 – 1.61 (m, 2H)。
3-{1-[4-((S)-2-二甲基氨基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 (“A323”)
UPLC/MS 0.51 min, [M+H]+ 479;
1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.30 (s, 1H), 9.11 (bs, 1H, NH+), 8.86 (s, 1H), 8.19 – 8.13 (m, 2H), 8.10 (dd, J = 11.0, 8.6 Hz, 1H), 7.86– 7.76 (m, 2H), 7.34 (dd, J = 11.4, 7.1 Hz, 1H), 4.64 – 4.54 (m, 1H), 3.64 –3.54 (m, 1H), 3.51 – 3.39 (m, 2H), 3.28 – 2.16 (m, 1H), 3.08 – 2.80 (m, 6H),2.22 – 2.10 (m, 1H), 2.01 – 1.88 (m, 1H), 1.86 – 1.68 (m, 2H)。
3-{1-[4-((S)-2-二甲基氨基甲基-吡咯烷-1-羰基)-苯基]-1H-吡唑-4-基}-6-氟-1H-喹啉-2-酮 (“A324”)
UPLC/MS 0.51 min, [M+H]+ 460;
1H NMR (400 MHz, DMSO-d 6) δ 12.12 (s, 1H), 9.21 (s, 1H), 9.12 (bs, 1H, NH+), 8.48 (s, 1H), 8.42 (s, 1H), 8.10 – 7.96 (m, 2H), 7.84 – 7.66 (m, 2H),7.50 (dd, J = 8.5, 1.9 Hz, 1H), 7.44 – 7.30 (m, 2H), 4.63 – 4.54 (m, 1H),3.66 – 3.56 (m, 1H), 3.55 – 3.14 (m, 3H), 3.01 (d, J = 4.2 Hz, 3H), 2.88 (d,J = 4.2 Hz, 3H), 2.22 – 2.11 (m, 1H), 2.04 – 1.87 (m, 1H), 1.85 – 1.66 (m,2H)。
3-{1-[4-((R)-2-二甲基氨基甲基-吡咯烷-1-羰基)-苯基]-1H-吡唑-4-基}-6-氟-1H-喹啉-2-酮 (“A325”)
UPLC/MS 0.51 min, [M+H]+ 460;
1H NMR (400 MHz, DMSO-d 6) δ 12.12 (s, 1H), 9.21 (s, 1H), 9.12 (bs, 1H, NH+), 8.48 (s, 1H), 8.42 (s, 1H), 8.10 – 7.96 (m, 2H), 7.84 – 7.66 (m, 2H),7.50 (dd, J = 8.5, 1.9 Hz, 1H), 7.44 – 7.30 (m, 2H), 4.63 – 4.54 (m, 1H),3.66 – 3.56 (m, 1H), 3.55 – 3.14 (m, 3H), 3.01 (d, J = 4.2 Hz, 3H), 2.88 (d,J = 4.2 Hz, 3H), 2.22 – 2.11 (m, 1H), 2.04 – 1.87 (m, 1H), 1.85 – 1.66 (m,2H)。
实施例21
3-{1-[4-((S)-3-二甲基氨基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A326”)
UPLC/MS 0.46 min, [M+H]+ 461;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.22 (s, 1H), 8.77 (s, 1H), 8.11 –7.97 (m, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.59 (dd, J = 9.2, 2.8 Hz, 1H), 7.40(dd, J = 9.0, 4.7 Hz, 1H), 7.28 (td, J = 8.8, 2.8 Hz, 1H), 3.87 – 3.07 (m,6H), 2.87 – 2.57 (m, 7H), 2.16 – 2.01 (m, 1H), 1.74 – 1.59 (m, 1H)。
类似地制备以下化合物:
6-氟-3-{1-[4-((顺)-5-甲基-六氢-吡咯并[3,4-c]吡咯-2-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A327”)
HPLC/MS 1.26 min (A), [M+H]+ 459;
1H NMR (500 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H),8.17 (s, 1H), 8.12 – 8.04 (m, 2H), 7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.75 –7.64 (m, 2H), 7.48 – 7.40 (m, 2H), 3.79 (bs, 1H), 3.67 (bs, 1H), 3.48 (bs,1H), 3.31 (bs, 1H), 2.82 (bs, 2H), 2.52 – 2.34 (m, 4H), 2.25 (s, 3H)。
3-{1-[4-((R)-3-二甲基氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 (“A328”)
HPLC/MS 1.23 min (A), [M+H]+ 479;
1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.26 (s, 1H), 8.84 (s, 1H),8.12 – 8.05 (m, 3H), 7.60 (d, J = 8.1 Hz, 2H), 7.32 (dd, J = 11.4, 7.1 Hz,1H), 4.5 – 4-2 (m, 1H), 3.77 – 2.74 (m, 4H), 2.32 – 2.02 (m, 7H), 1.85 – 1.62(m, 1H), 1.73 (d, J = 36.7 Hz, 1H), 1.54 – 1.34 (m, 2H)。
3-{1-[4-((S)-3-二甲基氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 (“A329”)
HPLC/MS 1.25 min (A), [M+H]+ 479;
1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.26 (s, 1H), 8.84 (s, 1H),8.12 – 8.05 (m, 3H), 7.60 (d, J = 8.1 Hz, 2H), 7.32 (dd, J = 11.4, 7.1 Hz,1H), 4.5 – 4-2 (m, 1H), 3.77 – 2.74 (m, 4H), 2.32 – 2.02 (m, 7H), 1.85 – 1.62(m, 1H), 1.73 (d, J = 36.7 Hz, 1H), 1.54 – 1.34 (m, 2H)。
3-{1-[4-(6-二甲基氨基-3-氮杂-双环[3.1.0]己烷-3-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A330”)
MS [M+H]+ 459;
1H NMR (500 MHz, DMSO-d 6) δ 12.27 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H),8.07 (d, J = 8.6 Hz, 2H), 7.80 (dd, J = 9.2, 2.7 Hz, 1H), 7.68 (d, J = 8.7Hz, 2H), 7.51 – 7.37 (m, 2H), 3.90 (d, J = 12.1 Hz, 1H), 3.70 (dd, J = 10.7,4.4 Hz, 1H), 3.44 (dd, J = 12.2, 4.5 Hz, 1H), 3.37 (d, J = 10.6 Hz, 1H), 2.21(s, 6H), 1.70 – 1.57 (m, 2H), 1.35 (t, J = 2.1 Hz, 1H)。
3-{1-[4-((R)-3-二甲基氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A331”)
HPLC/MS 1.21 min (A), [M+H]+ 461;
1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.29 (s, 1H), 8.86 (s, 1H),8.09 (d, J = 8.4 Hz, 2H), 7.81 (dd, J = 9.3, 2.7 Hz, 1H), 7.61 (d, J = 8.1Hz, 2H), 7.53 – 7.39 (m, 2H), 4.71 – 0.89 (m, 15H)。
3-{1-[4-((S)-3-二甲基氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A332”)
HPLC/MS 1.19 min (A), [M+H]+ 461;
1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.29 (s, 1H), 8.86 (s, 1H),8.09 (d, J = 8.4 Hz, 2H), 7.81 (dd, J = 9.3, 2.7 Hz, 1H), 7.61 (d, J = 8.1Hz, 2H), 7.53 – 7.39 (m, 2H), 4.71 – 0.89 (m, 15H)。
3-{1-[4-((R)-3-二甲基氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-7-氟-1H-喹啉-2-酮 (“A333”)
UPLC/MS 0.46 min, [M+H]+ 461;
1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.24 (s, 1H), 8.86 (s, 1H),8.08 (d, J = 8.2 Hz, 2H), 8.00 (dd, J = 9.6, 6.1 Hz, 1H), 7.60 (d, J = 8.1Hz, 2H), 7.27 – 6.99 (m, 2H), 4.71 – 0.89 (m, 15H)。
3-{1-[4-((R)-3-二甲基氨基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A334”)
UPLC/MS 0.46 min, [M+H]+ 461;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.22 (s, 1H), 8.77 (s, 1H), 8.11 –7.97 (m, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.59 (dd, J = 9.2, 2.8 Hz, 1H), 7.40(dd, J = 9.0, 4.7 Hz, 1H), 7.28 (td, J = 8.8, 2.8 Hz, 1H), 3.87 – 3.07 (m,6H), 2.87 – 2.57 (m, 7H), 2.16 – 2.01 (m, 1H), 1.74 – 1.59 (m, 1H)。
3-{1-[4-((R)-3-二甲基氨基甲基-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6,7-二氟-1H-喹啉-2-酮 (“A335”)
UPLC/MS 0.48 min, [M+H]+ 479;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.18 (s, 1H), 8.75 (s, 1H), 8.07 –7.96 (m, 2H), 7.80 (dd, J = 10.8, 8.4 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.28(dd, J = 11.4, 7.0 Hz, 1H), 3.87 – 3.07 (m, 6H), 2.87 – 2.57 (m, 7H), 2.16 –2.01 (m, 1H), 1.74 – 1.59 (m, 1H)。
3-{1-[4-((S)-3-二甲基氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-7-氟-1H-喹啉-2-酮 (“A336”)
UPLC/MS 0.48 min, [M+H]+ 461;
1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.24 (s, 1H), 8.86 (s, 1H),8.08 (d, J = 8.2 Hz, 2H), 8.00 (dd, J = 9.6, 6.1 Hz, 1H), 7.60 (d, J = 8.1Hz, 2H), 7.27 – 6.99 (m, 2H), 4.71 – 0.89 (m, 15H)。
3-{1-[4-((S)-3-二乙基氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A337”)
HPLC/MS 1.25 min (A), [M+H]+ 489;
1H NMR (500 MHz, DMSO-d6) δ 12.29 (s, 1H), 9.30 (d, J = 2.5 Hz, 1H), 8.86(s, 1H), 8.10 (d, J = 8.0 Hz, 2H), 7.81 (dd, J = 9.2, 2.7 Hz, 1H), 7.71 –7.58 (m, 2H), 7.55 – 7.33 (m, 2H), 4.60 – 4.35 (m, 1H), 3.62 – 3.46 (m, 1H),3.08 – 2.90 (m, 1H), 2.78 – 2.34 (m, 6H), 2.03 – 1.38 (m, 4H), 0.94 (d, J =69.7 Hz, 6H)。
3-{1-[4-((R)-3-二乙基氨基-哌啶-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A338”)
HPLC/MS 1.24 min (A), [M+H]+ 489;
1H NMR (500 MHz, DMSO-d6) δ 12.29 (s, 1H), 9.30 (d, J = 2.5 Hz, 1H), 8.86(s, 1H), 8.10 (d, J = 8.0 Hz, 2H), 7.81 (dd, J = 9.2, 2.7 Hz, 1H), 7.71 –7.58 (m, 2H), 7.55 – 7.33 (m, 2H), 4.60 – 4.35 (m, 1H), 3.62 – 3.46 (m, 1H),3.08 – 2.90 (m, 1H), 2.78 – 2.34 (m, 6H), 2.03 – 1.38 (m, 4H), 0.94 (d, J =69.7 Hz, 6H)。
3-{1-[4-(4-二甲基氨基-3,3-二氟-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A339”)
HPLC/MS 1.27 min (A), [M+H]+ 483;
1H NMR (700 MHz, DMSO-d 6) 旋转异构体的1:1混合物, δ 12.31 (s, 1H), 9.32(s, 1H), 8.87 (s, 1H), 8.12 (d, J = 8.3 Hz, 2H), 7.85 – 7.78 (m, 3H), 7.47(td, J = 8.7, 2.8 Hz, 1H), 7.43 (dd, J = 9.1, 4.8 Hz, 1H), 4.21 – 3.78 (m,3H), 3.68 (t, J = 10.1 Hz, 0.5H), 3.47 (t, J = 10.9 Hz, 0.5H), 3.23 (dq, J =17.7, 9.0 Hz, 1H), 2.33 (s, 3H), 2.24 (s, 3H)。
3-{1-[4-((S)-3-二甲基氨基甲基-吡咯烷-1-羰基)-苯基]-1H-吡唑-4-基}-6-氟-1H-喹啉-2-酮 (“A340”)
UPLC/MS 0.48 min, [M+H]+ 460;
1H NMR (500 MHz, DMSO-d 6) 旋转异构体的1:1混合物,信号的选择 δ 12.16 (s,1H), 9.20 (s, 1H), 8.47 (s, 1H), 8.43 (s, 1H), 7.99 – 7.90 (m, 2H), 7.78 –7.65 (m, 2H), 7.50 (dd, J = 9.0, 2.5 Hz, 1H), 7.45 – 7.32 (m, 2H), 2.18 (s,3H), 2.08 (s, 3H)。
3-{1-[4-((反)-3-二甲基氨基-4-氟-吡咯烷-1-羰基)-苯基]-1H-[1,2,3]三唑-4-基}-6-氟-1H-喹啉-2-酮 (“A341”)
HPLC/MS 1.23 min (A), [M+H]+ 465;
1H NMR (500 MHz, DMSO-d6) 旋转异构体的1:1混合物 δ 12.32 (s, 1H), 9.32 (s,1H), 8.87 (s, 1H), 8.24 – 7.95 (m, 2H), 7.86 – 7.76 (m, 3H), 7.47 (td, J =8.8, 2.8 Hz, 1H), 7.43 (dd, J = 9.0, 4.9 Hz, 1H), 5.30 (m, 1H), 4.04 – 3.49(m, 4H), 3.05 – 2.92 (m, 1H), 2.26 (s, 3H), 2.16 (s, 3H)。
实施例22
6-氟-3-[1-(4-甲基氨基-苯基)-1H-[1,2,3]三唑-4-基]-1H-喹啉-2-酮 (“A342”)和(R)-四氢-呋喃-2-甲酸{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯基}-甲基-酰胺 (“A343”)
“A342”: MS [M+H]+ 336;
1H NMR (400 MHz, DMSO-d 6) δ 12.22 (s, 1H), 8.98 (s, 1H), 8.80 (s, 1H),7.80 – 7.74 (m, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.46 – 7.38 (m, 2H), 6.79 (d,J = 8.6 Hz, 2H), 4.07 (br. s, 1H), 2.50 (p, J = 1.9 Hz, 3H)。
“A343”: MS [M+H]+ 434;
1H NMR (400 MHz, DMSO-d 6) δ 12.26 (s, 1H), 9.26 (s, 1H), 8.84 (s, 1H),8.08 (d, J = 8.6 Hz, 2H), 7.79 (dd, J = 9.3, 2.6 Hz, 1H), 7.58 (d, J = 8.6Hz, 2H), 7.49 – 7.39 (m, 2H), 4.29 (br. s, 1H), 3.81 (q, J = 7.1 Hz, 1H),3.69 (br. s, 1H), 3.25 (s, 3H), 2.01 (br. s, 1H), 1.96 – 1.80 (m, 2H), 1.73(br. s, 1H)。
类似地制备以下化合物:
(S)-四氢-呋喃-2-甲酸{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯基}-甲基-酰胺 (“A344”)
MS [M+H]+ 434;
1H NMR (400 MHz, DMSO-d 6) δ 12.26 (s, 1H), 9.26 (s, 1H), 8.84 (s, 1H),8.08 (d, J = 8.6 Hz, 2H), 7.79 (dd, J = 9.3, 2.6 Hz, 1H), 7.58 (d, J = 8.6Hz, 2H), 7.49 – 7.39 (m, 2H), 4.29 (br. s, 1H), 3.81 (q, J = 7.1 Hz, 1H),3.69 (br. s, 1H), 3.25 (s, 3H), 2.01 (br. s, 1H), 1.96 – 1.80 (m, 2H), 1.73(br. s, 1H)。
四氢-吡喃-4-甲酸{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯基}-甲基-酰胺 (“A345”)
MS [M+H]+ 448;
1H NMR (400 MHz, DMSO-d 6) δ 12.27 (s, 1H), 9.27 (s, 1H), 8.85 (s, 1H),8.09 (d, J = 8.6 Hz, 2H), 7.80 (dd, J = 9.2, 2.6 Hz, 1H), 7.59 (d, J = 8.5Hz, 2H), 7.50 – 7.39 (m, 2H), 3.78 (d, J = 11.3 Hz, 2H), 3.23 (s, 3H), 3.11(br. s, 2H), 1.65 (qd, J = 12.3, 4.4 Hz, 2H), 1.58 – 1.43 (m, 2H)。
(R)-N-{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯基}-2-甲氧基-N-甲基-丙酰胺 (“A346”)
MS [M+H]+ 422;
1H NMR (400 MHz, DMSO-d 6) δ 12.24 (s, 1H), 9.27 (s, 1H), 8.85 (s, 1H),8.10 (d, J = 8.6 Hz, 2H), 7.80 (dd, J = 9.2, 2.6 Hz, 1H), 7.59 (d, J = 8.7Hz, 2H), 7.50 – 7.39 (m, 2H), 3.88 (br. s, 1H), 3.26 (s, 3H), 3.08 (s, 3H),1.16 (br. s, 3H)。
(2S,4S)-4-甲氧基-吡咯烷-2-甲酸{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯基}-甲基-酰胺 (“A347”)
MS [M+H]+ 463; 盐酸盐
1H NMR (700 MHz, DMSO-d 6 + CF3COOD) δ 9.34 (s, 1H), 8.88 (s, 1H), 8.22 (d,J = 8.4 Hz, 2H), 7.78 (dd, J = 9.1, 2.8 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H),7.50 – 7.40 (m, 2H), 4.26 (dd, J = 10.3, 6.9 Hz, 1H), 3.94 (br. s, 1H), 3.48– 3.38 (m, 1H), 3.34 (s, 3H), 3.22 (s, 3H), 3.13 (dd, J = 12.4, 4.7 Hz, 1H),2.07 (ddd, J = 16.0, 10.5, 6.1 Hz, 1H), 1.95 – 1.84 (m, 1H)。
(S)-N-{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯基}-2-甲氧基-N-甲基-丙酰胺 (“A348”)
MS [M+H]+ 422;
1H NMR (400 MHz, DMSO-d 6) δ 1H NMR (400 MHz, DMSO-d 6) δ 12.24 (s, 1H),9.27 (s, 1H), 8.85 (s, 1H), 8.10 (d, J = 8.6 Hz, 2H), 7.80 (dd, J = 9.2, 2.6Hz, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.50 – 7.39 (m, 2H), 3.88 (br. s, 1H),3.26 (s, 3H), 3.08 (s, 3H), 1.16 (br. s, 3H)。
1-甲基-哌啶-4-甲酸{4-[4-(6-氟-2-氧代-1,2-二氢-喹啉-3-基)-[1,2,3]三唑-1-基]-苯基}-甲基-酰胺 (“A349”)
MS [M+H]+ 461; 盐酸盐
1H NMR (500 MHz, DMSO-d 6) δ 12.34 (s, 1H), 9.76 (s, 1H), 9.30 (s, 1H),8.86 (s, 1H), 8.15 (d, J = 7.5 Hz, 2H), 7.82 (dd, J = 9.2, 2.8 Hz, 1H), 7.65(d, J = 6.6 Hz, 2H), 7.52 – 7.41 (m, 2H), 3.35 – 3.26 (m, 2H), 3.22 (s, 3H),2.82 – 2.67 (m, 2H), 2.61 (s, 3H), 2.44 (br. s, 1H), 1.99 – 1.74 (m, 4H)。
实施例23
6-氟-3-{1-[5-((S)-3-甲氧基-吡咯烷-1-羰基)-噻吩-3-基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A350”)
UPLC/MS 0.70 min, [M+H]+ 440;
1H NMR (500 MHz, DMSO-d6) 旋转异构体的1:1混合物 δ 12.30 (s, 1H), 9.35 (s,0.5H), 9.34 (s, 0.5H), 8.85 (s, 1H), 8.42 (d, J = 1.4 Hz, 1H), 8.22 (d, J =1.5 Hz, 0.5H), 8.19 (d, J = 1.5 Hz, 0.5H), 7.82 (dd, J = 9.3, 2.8 Hz, 1H),7.46 (td, J = 8.8, 2.8 Hz, 1H), 7.42 (dd, J = 9.1, 4.9 Hz, 1H), 4.20 – 3.87(m, 3H), 3.75 – 3.47 (m, 2H), 3.29 (s, 1.5H), 3.27 (s, 1.5H), 2.25 – 1.90 (m,2H)。
类似地制备以下化合物:
6-氟-3-{1-[5-((R)-3-甲氧基-吡咯烷-1-羰基)-噻吩-3-基]-1H-[1,2,3]三唑-4-基}-1H-喹啉-2-酮 (“A351”)
UPLC/MS 0.71 min, [M+H]+ 440;
1H NMR (500 MHz, DMSO-d6) 旋转异构体的1:1混合物 δ 12.30 (s, 1H), 9.35 (s,0.5H), 9.34 (s, 0.5H), 8.85 (s, 1H), 8.42 (d, J = 1.4 Hz, 1H), 8.22 (d, J =1.5 Hz, 0.5H), 8.19 (d, J = 1.5 Hz, 0.5H), 7.82 (dd, J = 9.3, 2.8 Hz, 1H),7.46 (td, J = 8.8, 2.8 Hz, 1H), 7.42 (dd, J = 9.1, 4.9 Hz, 1H), 4.20 – 3.87(m, 3H), 3.75 – 3.47 (m, 2H), 3.29 (s, 1.5H), 3.27 (s, 1.5H), 2.25 – 1.90 (m,2H)。
以下实施例涉及药物:
实施例A:注射小瓶
将100 g式I的活性成分和5 g磷酸氢二钠于3 l重蒸馏水中的溶液使用2 N盐酸调节至pH 6.5,无菌过滤,转移入注射小瓶中,在无菌条件下冻干,且在无菌条件下密封。各注射小瓶含有5 mg活性成分。
实施例B:栓剂
将20 g式I的活性成分与100 g大豆卵磷脂和1400 g可可脂的混合物熔化,倒入模具中且使之冷却。各栓剂含有20 mg活性成分。
实施例C:溶液
从1 g式I的活性成分、9.38 g NaH2PO4∙2 H2O、28.48 g Na2HPO4∙12 H2O和0.1 g苯扎氯铵在940 ml重蒸馏水中制备溶液。将pH调节至6.8,将溶液补足至1 l,且通过辐射灭菌。该溶液可以以滴眼剂的形式使用。
实施例D:软膏剂
在无菌条件下将500 mg式I的活性成分与99.5 g凡士林混合。
实施例E:片剂
以常规方式压制1 kg式I的活性成分、4 kg乳糖、1.2 kg马铃薯淀粉、0.2 kg滑石和0.1kg硬脂酸镁的混合物,使得以每片含有10 mg活性成分的方式得到片剂。
实施例F:糖衣丸
与实施例E类似地压制片剂,且随后以常规方式用蔗糖、马铃薯淀粉、滑石、黄蓍胶和染料的包衣进行包衣。
实施例G:胶囊剂
以使得各胶囊含有20 mg活性成分的方式,将2 kg式I的活性成分以常规方式引入硬明胶胶囊中。
实施例H:安瓿
将1 kg式I的活性成分于60 l重蒸馏水中的溶液无菌过滤,转移入安瓿中,在无菌条件下冻干,且在无菌条件下密封。各安瓿含有10 mg活性成分。
Claims (13)
1.式I的化合物
其中
X1、X2、X3、X4各自彼此独立地表示CH或N,
Y表示N或CH,
Q表示H或CH3,
R1表示H、F、Cl、Br、CN、CH3、CF3或OCH3,
R2表示H、F或Cl,
R3表示苯基、萘基、吡啶基、嘧啶基、喹啉基、异喹啉基、吲哚基、吲唑基、噻吩基、二氢异吲哚基或苯并咪唑基,其各自未被取代或被以下基团单-、双-或三取代:Hal、CN、NO2、A、(CR4)nOR4、(CR4)nN(R4)2、(CR4)nS(O)mR4、(CR4)nCON(R4)2、(CR4)nCOHet、(CR4)nSO2N(R4)2、(CR4)nSO2Het、(CR4)nN(R4)2、(CR4)nHet、O(CR4)nCOHet、(CR4)nO(CR4)nHet、(CR4)nN(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nN(R4)2、(CR4)nN(R4)COA、(CR4)nN(R4)COHet’、(CR4)nOCyc和/或(CR4)nCOOR4,
R4表示H或A’,
A表示具有1-10个C-原子的无支链或支链的烷基,其中两个相邻碳原子可以形成双键,和/或一个或两个不相邻的CH-和/或CH2-基团可以被N-、O-和/或S-原子替换,且其中1-7个H-原子可以被R5替换,
或具有3-7个C原子的环状烷基,
A’ 表示具有1-6个C-原子的无支链或支链的烷基,其中一个或两个不相邻的CH-和/或CH2-基团可以被O-原子替换,
Cyc 表示环丁基、环戊基或环己基,其各自未被取代或被以下基团单-或双取代:A、Hal、OR4、N(R4)2、Het’、(CR4)nO(CR4)nHet’、CON(R4)2和/或=O,
R5表示F、Cl或OH,
Het 表示吡咯烷基、吗啉基、哌啶基、哌嗪基、[1,4]-二氮杂环庚烷基、噁唑烷基、六氢-吡咯并[3,4-c]吡咯基、2-氧杂-6-氮杂-螺[3.4]辛基、2-氧杂-6-氮杂-螺[3.5]壬基、2-氧杂-7-氮杂-螺[3.5]壬基、2,5-二氧杂-8-氮杂-螺[3.5]壬基、氧杂环丁烷基、2-氧杂-5-氮杂-螺[3.4]辛基、2-氧杂-6-氮杂-螺[3.3]庚基、3-氮杂-双环[3.1.0]己基、2-氧杂-7-氮杂-螺[3.5]壬基、异噁唑烷基、氮杂环丁烷基、2,6-二氮杂-螺[3.4]辛基、六氢-吡咯并[3,4-b]吡咯基、四氢呋喃基或异噻唑烷基,其各自未被取代或被以下基团单-、双-或三取代:A、Hal、OR4、OCOA、COA、(CR4)nN(R4)2、(CR4)nHet’、(CR4)nO(CR4)nHet’、CON(R4)2、COHet’、(CR4)nS(O)mR4和/或=O,
Het’表示吡咯烷基、吗啉基、哌啶基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基、吡啶基、吡唑基或哌嗪基,其各自未被取代或被以下基团单-或双取代:A、Hal、OR4、N(R4)2和/或=O,
Hal 表示F、Cl、Br或I,
n表示0、1、2或3,
m表示0、1或2,
条件是X1、X2、X3、X4中的仅一个或两个表示N,
和其药学上可接受的盐、互变异构体和立体异构体,包括其所有比率的混合物。
2.根据权利要求1所述的化合物,其中
R1表示H、F、Cl、Br、CN、CH3、CF3或OCH3,
R2表示H或F,
和其药学上可接受的溶剂化物、盐、互变异构体和立体异构体,包括其所有比率的混合物。
3.根据权利要求1或2所述的化合物,其中
R3表示苯基、吡啶基、嘧啶基、吲哚基、吲唑基、噻吩基、二氢异吲哚基或苯并咪唑基,其各自未被取代或被以下基团单-、双-或三取代:Hal、A、(CR4)nOR4、(CR4)nN(R4)2、(CR4)nS(O)mR4、(CR4)nCON(R4)2、(CR4)nCOHet、(CR4)nSO2Het、(CR4)nHet、O(CR4)nCOHet、(CR4)nO(CR4)nHet、(CR4)nN(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nN(R4)2、(CR4)nN(R4)COA、(CR4)nN(R4)COHet’、(CR4)nOCyc和/或(CR4)nCOOR4,
和其药学上可接受的盐、互变异构体和立体异构体,包括其所有比率的混合物。
4.根据权利要求1-3中一项或多项所述的化合物,其中
A表示具有1-10个C-原子的无支链或支链的烷基,其中两个相邻碳原子可以形成双键,和/或一个或两个不相邻的CH-和/或CH2-基团可以被N-和/或O-原子替换,且其中1-7个H-原子可以被R5替换,
和其药学上可接受的盐、互变异构体和立体异构体,包括其所有比率的混合物。
5.根据权利要求1-4中一项或多项所述的化合物,其中
Het’表示吡咯烷基,
和其药学上可接受的盐、互变异构体和立体异构体,包括其所有比率的混合物。
6.根据权利要求1-5中一项或多项所述的化合物,其中
X1、X2、X3、X4各自彼此独立地表示CH或N,
Y表示N或CH,
Q表示H或CH3,
R1表示H、F、Cl、Br、CN、CH3、CF3或OCH3,
R2表示H或F,
R3表示苯基、吡啶基、嘧啶基、吲哚基、吲唑基、噻吩基、二氢异吲哚基或苯并咪唑基,其各自未被取代或被以下基团单-、双-或三取代:Hal、A、(CR4)nOR4、(CR4)nN(R4)2、(CR4)nS(O)mR4、(CR4)nCON(R4)2、(CR4)nCOHet、(CR4)nSO2Het、(CR4)nHet、O(CR4)nCOHet、(CR4)nO(CR4)nHet、(CR4)nN(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nHet、(CR4)nCON(R4)(CR4)nN(R4)2、(CR4)nN(R4)COA、(CR4)nN(R4)COHet’、(CR4)nOCyc和/或(CR4)nCOOR4,
R4表示H或A’,
A表示具有1-10个C-原子的无支链或支链的烷基,其中两个相邻碳原子可以形成双键,和/或一个或两个不相邻的CH-和/或CH2-基团可以被N-和/或O-原子替换,且其中1-7个H-原子可以被R5替换,
Cyc 表示环丁基、环戊基或环己基,其各自未被取代或被以下基团单-或双取代:A、Hal、OR4、N(R4)2、Het’、(CR4)nO(CR4)nHet’、CON(R4)2和/或=O,
A’ 表示具有1-6个C-原子的无支链或支链的烷基,其中一个或两个不相邻的CH-和/或CH2-基团可以被O-原子替换,
R5表示F、Cl或OH,
Het 表示吡咯烷基、吗啉基、哌啶基、哌嗪基、[1,4]-二氮杂环庚烷基、噁唑烷基、六氢-吡咯并[3,4-c]吡咯基、2-氧杂-6-氮杂-螺[3.4]辛基、2-氧杂-6-氮杂-螺[3.5]壬基、2-氧杂-7-氮杂-螺[3.5]壬基、2,5-二氧杂-8-氮杂-螺[3.5]壬基、氧杂环丁烷基、2-氧杂-5-氮杂-螺[3.4]辛基、2-氧杂-6-氮杂-螺[3.3]庚基、3-氮杂-双环[3.1.0]己基、2-氧杂-7-氮杂-螺[3.5]壬基、异噁唑烷基、氮杂环丁烷基、2,6-二氮杂-螺[3.4]辛基、六氢-吡咯并[3,4-b]吡咯基、四氢呋喃基或异噻唑烷基,其各自未被取代或被以下基团单-、双-或三取代:A、Hal、OR4、OCOA、COA、(CR4)nN(R4)2、(CR4)nHet’、(CR4)nO(CR4)nHet’、CON(R4)2、COHet’、(CR4)nS(O)mR4和/或=O,
Het’表示吡咯烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基、吡啶基或吡唑基,
Hal 表示F、Cl、Br或I,
n表示0、1、2或3,
m表示0、1或2,
和其药学上可接受的盐、互变异构体和立体异构体,包括其所有比率的混合物。
7.根据权利要求1所述的化合物,其选自:
和其药学上可接受的溶剂化物、盐、互变异构体和立体异构体,包括其所有比率的混合物。
8.用于制备根据权利要求1-7所述的式I化合物及其药学上可接受的盐、溶剂化物、互变异构体和立体异构体的方法,其特征在于
a) 对于式I的化合物的制备,
其中
X1、X2、X3、X4 表示CH且
Y表示N,
使式II的化合物
其中R1、R2和Q具有权利要求1中所示的含义,
与式III的化合物反应,
N3-R3 III
其中R3具有权利要求1中所示的含义,
或者
b) 对于式I的化合物的制备,
其中
Y表示N,
使式IV的化合物
其中
且X1、X2、X3、X4、R1、R2和Q具有权利要求1中所示的含义,
与式V的化合物反应
其中R3具有权利要求1中所示的含义,
或者
c) 基团R3通过如下转化为另一基团R3:
i) 将羧基基团转化为酰胺,
ii) 将氨基基团酰化或烷基化,
或者
d) 通过用溶剂分解剂或氢解剂处理来将式I的化合物从其官能衍生物之一释放,
和/或
式I的碱或酸被转化为其盐之一。
9.药物,其包含至少一种根据权利要求1的式I的化合物和/或其药学上可接受的盐、溶剂化物、互变异构体和立体异构体,包括它们的所有比率的混合物,和任选地药学上可接受的载体、赋形剂或媒介物。
10.根据权利要求1的式I的用于应用的化合物及其药学上可接受的盐、溶剂化物、互变异构体和立体异构体,包括它们的所有比率的混合物,其用于治疗和/或预防癌症。
11.根据权利要求10的用于应用的化合物,其用于治疗和/或预防癌症,其中所述癌症是胃肠道间质瘤。
12.药物,其包含至少一种根据权利要求1的式I的化合物和/或其药学上可接受的盐、溶剂化物和立体异构体,包括它们的所有比率的混合物,和至少一种另外的药物活性成分。
13.套盒(试剂盒),其由如下的单独包装组成:
(a) 有效量的根据权利要求1的式I的化合物和/或其药学上可接受的盐、溶剂化物、盐和立体异构体,包括它们的所有比率的混合物,
和
(b) 有效量的另外的药物活性成分。
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CA3129665A1 (en) | 2019-03-21 | 2020-09-24 | Onxeo | A dbait molecule in combination with kinase inhibitor for the treatment of cancer |
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